Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 2; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. This cd is the second PH domain of AFAP. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 356 DVPTCGYLNVLSNNRWRERWCRVKDNKLIFHKDRTDLKTHIVSIPLRGCDVIPGLDSRHPLTFRLLRNGQEVAVLEASSS 435
Cdd:cd13307     1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                          90       100
                  ....*....|....*....|.
gi 1953360149 436 EDMGRWIGILLAETGSSTDPG 456
Cdd:cd13307    81 EDMGRWLGVLLAETGSATDPE 101

Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 2; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. This cd is the second PH domain of AFAP. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 356 DVPTCGYLNVLSNNRWRERWCRVKDNKLIFHKDRTDLKTHIVSIPLRGCDVIPGLDSRHPLTFRLLRNGQEVAVLEASSS 435
Cdd:cd13307     1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                          90       100
                  ....*....|....*....|.
gi 1953360149 436 EDMGRWIGILLAETGSSTDPG 456
Cdd:cd13307    81 EDMGRWLGVLLAETGSATDPE 101

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149  360 CGYLNVLSNN---RWRERWCRVKDNKLIFHKDRTDLK--THIVSIPLRGCDVIPGLDSR---HPLTFRLLRNGQEVAVLE 431
Cdd:smart00233   4 EGWLYKKSGGgkkSWKKRYFVLFNSTLLYYKSKKDKKsyKPKGSIDLSGCTVREAPDPDsskKPHCFEIKTSDRKTLLLQ 83

                           90
                   ....*....|....
gi 1953360149  432 ASSSEDMGRWIGIL 445
Cdd:smart00233  84 AESEEEREKWVEAL 97

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 360 CGYLNVLSNN---RWRERWCRVKDNKLIFHKDRTDLKTHI--VSIPLRGCDVIPGLDSR---HPLTFRLL---RNGQEVA 428
Cdd:pfam00169   4 EGWLLKKGGGkkkSWKKRYFVLFDGSLLYYKDDKSGKSKEpkGSISLSGCEVVEVVASDspkRKFCFELRtgeRTGKRTY 83

                          90
                  ....*....|....
gi 1953360149 429 VLEASSSEDMGRWI 442
Cdd:pfam00169  84 LLQAESEEERKDWI 97

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 567 NRVEADAKRLQSKEDELLKRKETLRNRLAQLRKERRDLRAAIEVNAGRKTQVV-----LEDKLKRLEEECKQKEAERVNL 641
Cdd:COG1196   277 EELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLEELEEELAELEeeleeLEEELEELEEELEEAEEELEEA 356

                          90
                  ....*....|....*.
gi 1953360149 642 ELELTEVTESLKKALA 657
Cdd:COG1196   357 EAELAEAEEALLEAEA 372

Ezrin/radixin/moesin, alpha-helical domain; The ERM family consists of three closely-related proteins, ezrin, radixin and moesin. Ezrin was first identified as a constituent of microvilli, radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions, and moesin as a heparin binding protein. A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein). ERM molecules contain 3 domains, an N-terminal globular domain, an extended alpha-helical domain and a charged C-terminal domain (pfam00769). Ezrin, radixin and merlin also contain a polyproline linker region between the helical and C-terminal domains. The N-terminal domain is highly conserved and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain. ERM proteins crosslink actin filaments with plasma membranes. They co-localize with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains. This is the alpha-helical domain, which is involved in intramolecular masking of protein-protein interaction sites, regulating the activity of this proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 574 KRLQSKEDELLKRKETLR---NRLAQLRKERRDLRAAIEVNAGRKTQvvLEDKLKRLEEECKQKEAERVNLELELTEVTE 650
Cdd:pfam20492  13 ERLKQYEEETKKAQEELEeseETAEELEEERRQAEEEAERLEQKRQE--AEEEKERLEESAEMEAEEKEQLEAELAEAQE 90

Actin filament associated protein family Pleckstrin homology (PH) domain, repeat 2; There are 3 members of the AFAP family of adaptor proteins: AFAP1, AFAP1L1, and AFAP1L2/XB130. AFAP1 is a cSrc binding partner and actin cross-linking protein. AFAP1L1 is thought to play a similar role to AFAP1 in terms of being an actin cross-linking protein, but it preferentially binds to cortactin and not cSrc, thereby playing a role in invadosome formation. AFAP1L2 is a cSrc binding protein, but does not bind to actin filaments. AFAP1L2 acts as an intermediary between the RET/PTC kinase and PI-3kinase pathway in the thyroid. The AFAPs share a similar structure of a SH3 binding motif, 3 SH2 binding motifs, 2 PH domains, a coiled-coil region corresponding to the AFAP1 leucine zipper, and an actin binding domain. This cd is the second PH domain of AFAP. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 356 DVPTCGYLNVLSNNRWRERWCRVKDNKLIFHKDRTDLKTHIVSIPLRGCDVIPGLDSRHPLTFRLLRNGQEVAVLEASSS 435
Cdd:cd13307     1 GVPTCGYLNVLVNQQWRSRWCCVKDGQLHFYQDRNKTKSPQQSLPLHGCEVVPGPDPKHPYSFRILRNGEEVAALEASSS 80

                          90       100
                  ....*....|....*....|.
gi 1953360149 436 EDMGRWIGILLAETGSSTDPG 456
Cdd:cd13307    81 EDMGRWLGVLLAETGSATDPE 101

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149  360 CGYLNVLSNN---RWRERWCRVKDNKLIFHKDRTDLK--THIVSIPLRGCDVIPGLDSR---HPLTFRLLRNGQEVAVLE 431
Cdd:smart00233   4 EGWLYKKSGGgkkSWKKRYFVLFNSTLLYYKSKKDKKsyKPKGSIDLSGCTVREAPDPDsskKPHCFEIKTSDRKTLLLQ 83

                           90
                   ....*....|....
gi 1953360149  432 ASSSEDMGRWIGIL 445
Cdd:smart00233  84 AESEEEREKWVEAL 97

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 164 KICAFLLRKK--RFGQWSKLLCVVKDTKLLCYKSS---KDQQPQMELPLQGCNVTYTPK-DSKKKKHELKI---TQQGTD 234
Cdd:pfam00169   2 VKEGWLLKKGggKKKSWKKRYFVLFDGSLLYYKDDksgKSKEPKGSISLSGCEVVEVVAsDSPKRKFCFELrtgERTGKR 81

                          90       100
                  ....*....|....*....|..
gi 1953360149 235 PLVLAVQSKEQAEQWLKVIRDV 256
Cdd:pfam00169  82 TYLLQAESEEERKDWIKAIQSA 103

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 168 FLLRKKRFG--QWSKLLCVVKDTKLLCYKSSKD--QQPQMELPLQGCnVTYTPKDSKKKKHELKITQQGTDPLVLAVQSK 243
Cdd:cd00821     4 YLLKRGGGGlkSWKKRWFVLFEGVLLYYKSKKDssYKPKGSIPLSGI-LEVEEVSPKERPHCFELVTPDGRTYYLQADSE 82

                          90
                  ....*....|
gi 1953360149 244 EQAEQWLKVI 253
Cdd:cd00821    83 EERQEWLKAL 92

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins pleckstrin homology (PH) domain, C-terminus; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Not much is known about FGD2. FGD1 is the best characterized member of the group with mutations here leading to the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 165 ICAFLLRKKRFGQWSKLLCVVKDTKLLC---YKSSKDQQPQMELPLQGCNVTYTPKDSK-KKKHELKITQQGTdPLVLAV 240
Cdd:cd13236    10 LCGFLQYSEKGKTWQKVWCVIPRTEPLVlylYGAPQDVRAQRTIPLPGCEVTVPPPEERlDGRHVFKLSQSKQ-SHYFSA 88

                          90
                  ....*....|....*
gi 1953360149 241 QSKEQAEQWLKVIRD 255
Cdd:cd13236    89 ESEELQQRWLEALSR 103

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 177 QWSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVT-YTPKDSKKKKHELKITQQGTDPLVLAVQSKEQAEQWLKVIRD 255
Cdd:cd13248    23 NWRKRWFVLKDNCLYYYKDPEEEKALGSILLPSYTISpAPPSDEISRKFAFKAEHANMRTYYFAADTAEEMEQWMNAMSL 102

Rho GTPase activating protein 25 and related proteins Pleckstrin homology (PH) domain; RhoGAP25 (also called ArhGap25) like other RhoGaps are involved in cell polarity, cell morphology and cytoskeletal organization. They act as GTPase activators for the Rac-type GTPases by converting them to an inactive GDP-bound state and control actin remodeling by inactivating Rac downstream of Rho leading to suppress leading edge protrusion and promotes cell retraction to achieve cellular polarity and are able to suppress RAC1 and CDC42 activity in vitro. Overexpression of these proteins induces cell rounding with partial or complete disruption of actin stress fibers and formation of membrane ruffles, lamellipodia, and filopodia. This hierarchy contains RhoGAP22, RhoGAP24, and RhoGAP25. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 355 EDVPTCGYLNVLSNN--RWRERWCRVKDNKLIFHKDRTDLKtHIVSIPLRGCDV-----------------IPGLDSRHP 415
Cdd:cd13263     1 ERPIKSGWLKKQGSIvkNWQQRWFVLRGDQLYYYKDEDDTK-PQGTIPLPGNKVkevpfnpeepgkflfeiIPGGGGDRM 79

                          90       100
                  ....*....|....*....|....*..
gi 1953360149 416 ltfrllRNGQEVAVLEASSSEDMGRWI 442
Cdd:cd13263    80 ------TSNHDSYLLMANSQAEMEEWV 100

Src kinase-associated phosphoprotein family Pleckstrin homology (PH) domain; Skap adaptor proteins couple receptors to cytoskeletal rearrangements. Src kinase-associated phosphoprotein of 55 kDa (Skap55)/Src kinase-associated phosphoprotein 1 (Skap1), Skap2, and Skap-homology (Skap-hom) have an N-terminal coiled-coil conformation, a central PH domain and a C-terminal SH3 domain. Their PH domains bind 3'-phosphoinositides as well as directly affecting targets such as in Skap55 where it directly affecting integrin regulation by ADAP and NF-kappaB activation or in Skap-hom where the dimerization and PH domains comprise a 3'-phosphoinositide-gated molecular switch that controls ruffle formation. PH domains are only found in eukaryotes. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 166 CAFLLRKKRFGQ-----WSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVTYTPKDSKKKKHEL--KITQQGTDPLVL 238
Cdd:cd13266     4 AGYLEKRRKDHSffgseWQKRWCAISKNVFYYYGSDKDKQQKGEFAINGYDVRMNPTLRKDGKKDCcfELVCPDKRTYQF 83

                          90
                  ....*....|....*
gi 1953360149 239 AVQSKEQAEQWLKVI 253
Cdd:cd13266    84 TAASPEDAEDWVDQI 98

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1953360149 371 WRERWCRVKDNKLIFHKDRTDLKThIVSIPLRG---CDVIPGLDSRHPLTFRLLRNGQEVAVLEASSSEDMGRWI 442
Cdd:cd13248    24 WRKRWFVLKDNCLYYYKDPEEEKA-LGSILLPSytiSPAPPSDEISRKFAFKAEHANMRTYYFAADTAEEMEQWM 97

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 567 NRVEADAKRLQSKEDELLKRKETLRNRLAQLRKERRDLRAAIEVNAGRKTQVV-----LEDKLKRLEEECKQKEAERVNL 641
Cdd:COG1196   277 EELELELEEAQAEEYELLAELARLEQDIARLEERRRELEERLEELEEELAELEeeleeLEEELEELEEELEEAEEELEEA 356

                          90
                  ....*....|....*.
gi 1953360149 642 ELELTEVTESLKKALA 657
Cdd:COG1196   357 EAELAEAEEALLEAEA 372

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 569 VEADAKRLQSKEDELLKRKETLRNRLAQLR--KERRDLRAAIEVNAGRKTQvvLEDKLKRLEEECKQKEAERVNLELELT 646
Cdd:COG1579    57 LEKEIKRLELEIEEVEARIKKYEEQLGNVRnnKEYEALQKEIESLKRRISD--LEDEILELMERIEELEEELAELEAELA 134

                          90
                  ....*....|.
gi 1953360149 647 EVTESLKKALA 657
Cdd:COG1579   135 ELEAELEEKKA 145

Anillin Pleckstrin homology (PH) domain; Anillin (Rhotekin/RTKN; also called PLEKHK/Pleckstrin homology domain-containing family K) is an actin binding protein involved in cytokinesis. It interacts with GTP-bound Rho proteins and results in the inhibition of their GTPase activity. Dysregulation of the Rho signal transduction pathway has been implicated in many forms of cancer. Anillin proteins have a N-terminal HRI domain/ACC (anti-parallel coiled-coil) finger domain or Rho-binding domain binds small GTPases from the Rho family. The C-terminal PH domain helps target anillin to ectopic septin containing foci. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 178 WSKLLCVVKDTKLLCYKSSKDQQPQMElPLQGCNVT------YTPKDSKKKKHELKITQQGTDP---LVLAVQSKEQAEQ 248
Cdd:cd13249    20 WTRLYCVLKGGNLLCYYSPEEIEAKVE-PLLTIPINketrirAVEKDSKGRASSLSIINPYSGEevtHVLSADSREELQK 98

                  ..
gi 1953360149 249 WL 250
Cdd:cd13249    99 WM 100

phosphodiesterase; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 566 KNRVEADAKR----LQSKEDELLKRKETLRNRLAQLRKERRDLraaievNAGRKTQVVLEDKLKRLEEECKQKEAERVNl 641
Cdd:PRK12704   70 RNEFEKELRErrneLQKLEKRLLQKEENLDRKLELLEKREEEL------EKKEKELEQKQQELEKKEEELEELIEEQLQ- 142

                  ...
gi 1953360149 642 ELE 644
Cdd:PRK12704  143 ELE 145

Rho GTPase activating protein 2 Pleckstrin homology (PH) domain; RhoGAP2 (also called RhoGap22 or ArhGap22) are involved in cell polarity, cell morphology and cytoskeletal organization. They activate a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt, and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues resulting in regulation of cell motility. Members here contain an N-terminal PH domain followed by a RhoGAP domain and either a BAR or TATA Binding Protein (TBP) Associated Factor 4 (TAF4) domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 170 LRKKR--FGQWSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVT-YTPKDSKKKKHELKITQQGT----------DPL 236
Cdd:cd13378     9 LKKQRsiMKNWQQRWFVLRGDQLFYYKDEEETKPQGCISLQGSQVNeLPPNPEEPGKHLFEILPGGAgdrekvpmnhEAF 88

                          90       100
                  ....*....|....*....|
gi 1953360149 237 VLAVQSKEQAEQWLKVIRDV 256
Cdd:cd13378    89 LLMANSQSDMEDWVKAIRRV 108

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins pleckstrin homology (PH) domain, C-terminus; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Not much is known about FGD2. FGD1 is the best characterized member of the group with mutations here leading to the X-linked disorder known as faciogenital dysplasia (FGDY). Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP). FGD4 is one of the genes associated with Charcot-Marie-Tooth neuropathy type 4 (CMT4), a group of progressive motor and sensory axonal and demyelinating neuropathies that are distinguished from other forms of CMT by autosomal recessive inheritance. Those affected have distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 360 CGYLNVLSNNR-WRERWCRVKDNK---LIFHKDRTDLKTHiVSIPLRGCDVIP-----GLDSRHplTFRlLRNGQEVAVL 430
Cdd:cd13236    11 CGFLQYSEKGKtWQKVWCVIPRTEplvLYLYGAPQDVRAQ-RTIPLPGCEVTVpppeeRLDGRH--VFK-LSQSKQSHYF 86

                          90
                  ....*....|....*
gi 1953360149 431 EASSSEDMGRWIGIL 445
Cdd:cd13236    87 SAESEELQQRWLEAL 101

Myosin X Pleckstrin homology (PH) domain, repeat 2; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd contains the second PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 361 GYLNVLSNNRWRERWCRVKDNKLIFHKDRTDLKTHIVSIPLRGCDVIpgLDsRHPLTFRL-LRNGQEVAVLEASSSEDMG 439
Cdd:cd13296    10 GGSSTLSRRNWKSRWFVLRDTVLKYYENDQEGEKLLGTIDIRSAKEI--VD-NDPKENRLsITTEERTYHLVAESPEDAS 86

                  ....*.
gi 1953360149 440 RWIGIL 445
Cdd:cd13296    87 QWVNVL 92

Predicted nucleic acid-binding protein DR0291, contains C4-type Zn-ribbon domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 557 SNADQYKYGKNRVEADAKRLQSKEDELL---KRKETLRNRLAQLRKERRDLRAAievnagrktqvvLEDKLKRLEEECKQ 633
Cdd:COG1579    86 RNNKEYEALQKEIESLKRRISDLEDEILelmERIEELEEELAELEAELAELEAE------------LEEKKAELDEELAE 153

                          90       100
                  ....*....|....*....|...
gi 1953360149 634 KEAERVNLELELTEVTESLKKAL 656
Cdd:COG1579   154 LEAELEELEAEREELAAKIPPEL 176

FERM, RhoGEF and pleckstrin domain-containing protein 1 and related proteins Pleckstrin Homology (PH) domain, repeat 2; Members here include FARP1 (also called Chondrocyte-derived ezrin-like protein; PH domain-containing family C member 2), FARP2 (also called FIR/FERM domain including RhoGEF; FGD1-related Cdc42-GEF/FRG), and FARP6 (also called Zinc finger FYVE domain-containing protein 24). They are members of the Dbl family guanine nucleotide exchange factors (GEFs) which are upstream positive regulators of Rho GTPases. Little is known about FARP1 and FARP6, though FARP1 has increased expression in differentiated chondrocytes. FARP2 is thought to regulate neurite remodeling by mediating the signaling pathways from membrane proteins to Rac. It is found in brain, lung, and testis, as well as embryonic hippocampal and cortical neurons. FARP1 and FARP2 are composed of a N-terminal FERM domain, a proline-rich (PR) domain, Dbl-homology (DH), and two C-terminal PH domains. FARP6 is composed of Dbl-homology (DH), and two C-terminal PH domains separated by a FYVE domain. This hierarchy contains the second PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 165 ICAFLLRK-KRFGQWSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVTY-TPKDSKKKKHELKItQQGTDPLVLAVQS 242
Cdd:cd13235     5 MSGYLLRKfKNSNGWQKLWVVFTNFCLFFYKSHQDEFPLASLPLLGYSVGLpSEADNIDKDYVFKL-QFKSHVYFFRAES 83

                          90
                  ....*....|..
gi 1953360149 243 KEQAEQWLKVIR 254
Cdd:cd13235    84 EYTFERWMEVIR 95

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 556 SSNADQYKYGKNRVEADAKRLQSKEDELLKRKETLRNRLAQLRKERRDLRAAI-----EVNAGRKTQVVLEDKLKRLEEE 630
Cdd:COG4372    30 SEQLRKALFELDKLQEELEQLREELEQAREELEQLEEELEQARSELEQLEEELeelneQLQAAQAELAQAQEELESLQEE 109

                          90       100
                  ....*....|....*....|....
gi 1953360149 631 CKQKEAERVNLELELTEVTESLKK 654
Cdd:COG4372   110 AEELQEELEELQKERQDLEQQRKQ 133

Uncharacterized conserved protein YhaN, contains AAA domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 533 TGKGKTLSSQQKKvDSTAGVKRTSSNADQYKYGKNRVEadakRLQSKEDELLKRKETLRNRLAQLRKERRDLRAAIEVNA 612
Cdd:COG4717    62 QGRKPELNLKELK-ELEEELKEAEEKEEEYAELQEELE----ELEEELEELEAELEELREELEKLEKLLQLLPLYQELEA 136

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1953360149 613 GRKTQVVLEDKLKRLE---EECKQKEAERVNLELELTEVTESLKKALA 657
Cdd:COG4717   137 LEAELAELPERLEELEerlEELRELEEELEELEAELAELQEELEELLE 184

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 1; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 168 FLLRKKRFGQ-WSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVTYTPKDSKKKKHELKITQQGTDPLVLAVQSKEQA 246
Cdd:cd13301     8 YLVKKGHVVNnWKARWFVLKEDGLEYYKKKTDSSPKGMIPLKGCTITSPCLEYGKRPLVFKLTTAKGQEHFFQACSREER 87

                  ....*...
gi 1953360149 247 EQWLKVIR 254
Cdd:cd13301    88 DAWAKDIT 95

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from insects, spiders, mollusks, and nematodes. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 359 TCGYL-----NVLSNNRWRERWCRVKDNKLIFHKDRTDLKTHIVsIPLRG--CDVIPGLDSRhPLTFRLLRNGQeVAVLE 431
Cdd:cd13326     1 YQGWLyqrrrKGKGGGKWAKRWFVLKGSNLYGFRSQESTKADCV-IFLPGftVSPAPEVKSR-KYAFKVYHTGT-VFYFA 77

                          90
                  ....*....|....
gi 1953360149 432 ASSSEDMGRWIGIL 445
Cdd:cd13326    78 AESQEDMKKWLDLL 91

Fungal proteins Pleckstrin homology (PH) domain, repeat 2; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the second PH repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 170 LRKKRFGQWSKLLCVVKDTKLLCYKSSKDQQPQMELPL-QGCNVTYTPKDSKKKKHELK-ITQqgTDPLVLAVQSKEQAE 247
Cdd:cd13299    15 LKKKGVNQWKKYWLVLRNRSLSFYKDQSEYSPVKIIPIdDIIDVVELDPLSKSKKWCLQiITP--EKRIRFCADDEESLI 92

                  ...
gi 1953360149 248 QWL 250
Cdd:cd13299    93 KWL 95

Connector enhancer of KSR (Kinase suppressor of ras) (CNK) pleckstrin homology (PH) domain; CNK family members function as protein scaffolds, regulating the activity and the subcellular localization of RAS activated RAF. There is a single CNK protein present in Drosophila and Caenorhabditis elegans in contrast to mammals which have 3 CNK proteins (CNK1, CNK2, and CNK3). All of the CNK members contain a sterile a motif (SAM), a conserved region in CNK (CRIC) domain, and a PSD-95/DLG-1/ZO-1 (PDZ) domain, and a PH domain. A CNK2 splice variant CNK2A also has a PDZ domain-binding motif at its C terminus and Drosophila CNK (D-CNK) also has a domain known as the Raf-interacting region (RIR) that mediates binding of the Drosophila Raf kinase. This cd contains CNKs from insects, spiders, mollusks, and nematodes. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1953360149 165 ICAFLLRKKRFG----QWSKLLCVVKDTKLLCYKSSKDQQPQMELPLQGCNVTYTPkDSKKKKHELKITQQGTdPLVLAV 240
Cdd:cd13326     1 YQGWLYQRRRKGkgggKWAKRWFVLKGSNLYGFRSQESTKADCVIFLPGFTVSPAP-EVKSRKYAFKVYHTGT-VFYFAA 78