P-loop containing Nucleoside Triphosphate Hydrolases; Members of the P-loop NTPase domain superfamily are characterized by a conserved nucleotide phosphate-binding motif, also referred to as the Walker A motif (GxxxxGK[S/T], where x is any residue), and the Walker B motif (hhhh[D/E], where h is a hydrophobic residue). The Walker A and B motifs bind the beta-gamma phosphate moiety of the bound nucleotide (typically ATP or GTP) and the Mg2+ cation, respectively. The P-loop NTPases are involved in diverse cellular functions, and they can be divided into two major structural classes: the KG (kinase-GTPase) class which includes Ras-like GTPases and its circularly permutated YlqF-like; and the ASCE (additional strand catalytic E) class which includes ATPase Binding Cassette (ABC), DExD/H-like helicases, 4Fe-4S iron sulfur cluster binding proteins of NifH family, RecA-like F1-ATPases, and ATPases Associated with a wide variety of Activities (AAA). Also included are a diverse set of nucleotide/nucleoside kinase families.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:cd04146   11 GKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVYSITDRSSFDV 90

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381 104 SSSYLELLALHAKeTQRSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFEHVQHVFHEAVREARR 180
Cdd:cd04146   91 VSQLLQLIREIKK-RDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families; RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:cd04146   11 GKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVYSITDRSSFDV 90

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381 104 SSSYLELLALHAKeTQRSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFEHVQHVFHEAVREARR 180
Cdd:cd04146   91 VSQLLQLIREIKK-RDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   27 GKLSLTVKFLTKRFISEYDPNL-EDTYSSEETVDHQPVHLRVMDTADLdtprncER--------YLNwAHAFLVVYSVDS 97
Cdd:pfam00071  11 GKSSLLIRFTQNKFPEEYIPTIgVDFYTKTIEVDGKTVKLQIWDTAGQ------ERfralrplyYRG-ADGFLLVYDITS 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   98 RQSFDSSSSYLELLALHAKEtqrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVRE 177
Cdd:pfam00071  84 RDSFENVKKWVEEILRHADE---NVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTN-ENVEEAFEELARE 159

                  ...
gi 767984381  178 ARR 180
Cdd:pfam00071 160 ILK 162

small GTP-binding protein domain; Proteins with a small GTP-binding domain recognized by this model include Ras, RhoA, Rab11, translation elongation factor G, translation initiation factor IF-2, tetratcycline resistance protein TetM, CDC42, Era, ADP-ribosylation factors, tdhF, and many others. In some proteins the domain occurs more than once.This model recognizes a large number of small GTP-binding proteins and related domains in larger proteins. Note that the alpha chains of heterotrimeric G proteins are larger proteins in which the NKXD motif is separated from the GxxxxGK[ST] motif (P-loop) by a long insert and are not easily detected by this model. [Unknown function, General]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   27 GKLSLTVKFL-TKRFISEYDPNLEDTYSSE-ETVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVYSVDSRQSFDS 103
Cdd:TIGR00231  13 GKSTLLNSLLgNKGSITEYYPGTTRNYVTTvIEEDGKTYKFNLLDTAGQEDYDAIRRlYYPQVERSLRVFDIVILVLDVE 92

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 767984381  104 --SSSYLELLALHAKetqRSIPALLLGNKLDMAQYRQVTKaEGVALAGRFGCLFFEVSA 160
Cdd:TIGR00231  93 eiLEKQTKEIIHHAD---SGVPIILVGNKIDLKDADLKTH-VASEFAKLNGEPIIPLSA 147

Ras-related and Estrogen-Regulated Growth inhibitor (RERG) and Ras-like 11 (RasL11)-like families; RERG (Ras-related and Estrogen- Regulated Growth inhibitor) and Ras-like 11 are members of a novel subfamily of Ras that were identified based on their behavior in breast and prostate tumors, respectively. RERG expression was decreased or lost in a significant fraction of primary human breast tumors that lack estrogen receptor and are correlated with poor clinical prognosis. Elevated RERG expression correlated with favorable patient outcome in a breast tumor subtype that is positive for estrogen receptor expression. In contrast to most Ras proteins, RERG overexpression inhibited the growth of breast tumor cells in vitro and in vivo. RasL11 was found to be ubiquitously expressed in human tissue, but down-regulated in prostate tumors. Both RERG and RasL11 lack the C-terminal CaaX prenylation motif, where a = an aliphatic amino acid and X = any amino acid, and are localized primarily in the cytoplasm. Both are believed to have tumor suppressor activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLD---TPRNCERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:cd04146   11 GKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQqneDPESLERSLRWADGFVLVYSITDRSSFDV 90

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381 104 SSSYLELLALHAKeTQRSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFEHVQHVFHEAVREARR 180
Cdd:cd04146   91 VSQLLQLIREIKK-RDGEIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

Ras subfamily of RAS small GTPases; Similar in fold and function to the bacterial EF-Tu GTPase. p21Ras couples receptor Tyr kinases and G protein receptors to protein kinase cascades

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381    27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:smart00173  12 GKSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTAgqeEFSAMR--DQYMRTGEGFLLVYSITDRQSFEE 89

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381   104 SSSYLELLaLHAKETQrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVREARR 180
Cdd:smart00173  90 IKKFREQI-LRVKDRD-DVPIVLVGNKCDLESERVVSTEEGKELARQWGCPFLETSAKER-VNVDEAFYDLVREIRK 163

Ras family; Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See pfam00009 pfam00025, pfam00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   27 GKLSLTVKFLTKRFISEYDPNL-EDTYSSEETVDHQPVHLRVMDTADLdtprncER--------YLNwAHAFLVVYSVDS 97
Cdd:pfam00071  11 GKSSLLIRFTQNKFPEEYIPTIgVDFYTKTIEVDGKTVKLQIWDTAGQ------ERfralrplyYRG-ADGFLLVYDITS 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   98 RQSFDSSSSYLELLALHAKEtqrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVRE 177
Cdd:pfam00071  84 RDSFENVKKWVEEILRHADE---NVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTN-ENVEEAFEELARE 159

                  ...
gi 767984381  178 ARR 180
Cdd:pfam00071 160 ILK 162

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:PTZ00369  17 GKSALTIQFIQNHFIDEYDPTIEDSYRKQCVIDEETCLLDILDTAgqeEYSAMR--DQYMRTGQGFLCVYSITSRSSFEE 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381 104 SSSYLELLaLHAKETQRsIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFeHVQHVFHEAVREARRELE 183
Cdd:PTZ00369  95 IASFREQI-LRVKDKDR-VPMILVGNKCDLDSERQVSTGEGQELAKSFGIPFLETSAKQRV-NVDEAFYELVREIRKYLK 171

R-Ras2/TC21, M-Ras/R-Ras3; The M-Ras/R-Ras-like subfamily contains R-Ras2/TC21, M-Ras/R-Ras3, and related members of the Ras family. M-Ras is expressed in lympho-hematopoetic cells. It interacts with some of the known Ras effectors, but appears to also have its own effectors. Expression of mutated M-Ras leads to transformation of several types of cell lines, including hematopoietic cells, mammary epithelial cells, and fibroblasts. Overexpression of M-Ras is observed in carcinomas from breast, uterus, thyroid, stomach, colon, kidney, lung, and rectum. In addition, expression of a constitutively active M-Ras mutant in murine bone marrow induces a malignant mast cell leukemia that is distinct from the monocytic leukemia induced by H-Ras. TC21, along with H-Ras, has been shown to regulate the branching morphogenesis of ureteric bud cell branching in mice. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYSV-DSRQSFD 102
Cdd:cd04145   14 GKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAgqeEFSAMR--EQYMRTGEGFLLVFSVtDRGSFEE 91

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381 103 SSSSYLELLALHAKETqrsIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFeHVQHVFHEAVREAR 179
Cdd:cd04145   92 VDKFHTQILRVKDRDE---FPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETSAKDRV-NVDKAFHDLVRVIR 164

Ras Homolog Enriched in Brain (RheB) is a small GTPase; Rheb (Ras Homolog Enriched in Brain) subfamily. Rheb was initially identified in rat brain, where its expression is elevated by seizures or by long-term potentiation. It is expressed ubiquitously, with elevated levels in muscle and brain. Rheb functions as an important mediator between the tuberous sclerosis complex proteins, TSC1 and TSC2, and the mammalian target of rapamycin (TOR) kinase to stimulate cell growth. TOR kinase regulates cell growth by controlling nutrient availability, growth factors, and the energy status of the cell. TSC1 and TSC2 form a dimeric complex that has tumor suppressor activity, and TSC2 is a GTPase activating protein (GAP) for Rheb. The TSC1/TSC2 complex inhibits the activation of TOR kinase through Rheb. Rheb has also been shown to induce the formation of large cytoplasmic vacuoles in a process that is dependent on the GTPase cycle of Rheb, but independent of the TOR kinase, suggesting Rheb plays a role in endocytic trafficking that leads to cell growth and cell-cycle progression. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  25 HYGKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLDT----PRnceRYLNWAHAFLVVYSVDSRQS 100
Cdd:cd04137   11 SVGKSSLTVQFVEGHFVESYYPTIENTFSKIITYKGQEYHLEIVDTAGQDEysilPQ---KYSIGIHGYILVYSVTSRKS 87

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381 101 -FDSSSSYLELLALHAKEtqrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVREAR 179
Cdd:cd04137   88 fEVVKVIYDKILDMLGKE---SVPIVLVGNKSDLHMERQVSAEEGKKLAESWGAAFLESSAKEN-ENVEEAFELLIEEIE 163

                 .
gi 767984381 180 R 180
Cdd:cd04137  164 K 164

Rap1 family GTPase consists of Rap1a and Rap1b isoforms; The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature. Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules. Rap1 has also been shown to localize in the Golgi of rat fibroblasts, zymogen granules, plasma membrane, and the microsomal membrane of pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm. Rap1 plays a role in phagocytosis by controlling the binding of adhesion receptors (typically integrins) to their ligands. In yeast, Rap1 has been implicated in multiple functions, including activation and silencing of transcription and maintenance of telomeres. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment of Cdc42, which is required for formation of dendrites and axons. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---------DLdtprncerYLNWAHAFLVVYSVds 97
Cdd:cd04175   13 GKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAgteqftamrDL--------YMKNGQGFVLVYSI-- 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  98 rqsfDSSSSYLELLALH-----AKETQrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFeHVQHVFH 172
Cdd:cd04175   83 ----TAQSTFNDLQDLReqilrVKDTE-DVPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSAKAKI-NVNEIFY 156

                 ....*...
gi 767984381 173 EAVREARR 180
Cdd:cd04175  157 DLVRQINR 164

Rem, Rem2, Rad, Gem/Kir (RGK) subfamily of Ras GTPases; RGK subfamily. The RGK (Rem, Rem2, Rad, Gem/Kir) subfamily of Ras GTPases are expressed in a tissue-specific manner and are dynamically regulated by transcriptional and posttranscriptional mechanisms in response to environmental cues. RGK proteins bind to the beta subunit of L-type calcium channels, causing functional down-regulation of these voltage-dependent calcium channels, and either termination of calcium-dependent secretion or modulation of electrical conduction and contractile function. Inhibition of L-type calcium channels by Rem2 may provide a mechanism for modulating calcium-triggered exocytosis in hormone-secreting cells, and has been proposed to influence the secretion of insulin in pancreatic beta cells. RGK proteins also interact with and inhibit the Rho/Rho kinase pathway to modulate remodeling of the cytoskeleton. Two characteristics of RGK proteins cited in the literature are N-terminal and C-terminal extensions beyond the GTPase domain typical of Ras superfamily members. The N-terminal extension is not conserved among family members; the C-terminal extension is reported to be conserved among the family and lack the CaaX prenylation motif typical of membrane-associated Ras proteins. However, a putative CaaX motif has been identified in the alignment of the C-terminal residues of this CD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFI-SEYDPNLEDTYSSEETVDHQPVHLRVMDTADLDTPRNCERY-LNWAHAFLVVYSV-DSRQSFDS 103
Cdd:cd04148   12 GKSSLANIFTAGVYEdSAYEASGDDTYERTVSVDGEEATLVVYDHWEQEDGMWLEDScMQVGDAYVIVYSVtDRSSFEKA 91

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 767984381 104 SSSYLELLALHAKEtqrSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVREAR 179
Cdd:cd04148   92 SELRIQLRRARQAE---DIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQ-HNVDELFEGIVRQVR 163

Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B; H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRncERYLNWAHAFLVVYSVDSRQSFDS 103
Cdd:cd04138   13 GKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAgqeEYSAMR--DQYMRTGEGFLCVFAINSRKSFED 90

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 767984381 104 SSSYLELLaLHAKETQrSIPALLLGNKLDMAqYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVREAR 179
Cdd:cd04138   91 IHTYREQI-KRVKDSD-DVPMVLVGNKCDLA-ARTVSTRQGQDLAKSYGIPYIETSAKTR-QGVEEAFYTLVREIR 162

Ral (Ras-like) family containing highly homologous RalA and RalB; The Ral (Ras-like) subfamily consists of the highly homologous RalA and RalB. Ral proteins are believed to play a crucial role in tumorigenesis, metastasis, endocytosis, and actin cytoskeleton dynamics. Despite their high sequence similarity (>80% sequence identity), nonoverlapping and opposing functions have been assigned to RalA and RalBs in tumor migration. In human bladder and prostate cancer cells, RalB promotes migration while RalA inhibits it. A Ral-specific set of GEFs has been identified that are activated by Ras binding. This RalGEF activity is enhanced by Ras binding to another of its target proteins, phosphatidylinositol 3-kinase (PI3K). Ral effectors include RLIP76/RalBP1, a Rac/cdc42 GAP, and the exocyst (Sec6/8) complex, a heterooctomeric protein complex that is involved in tethering vesicles to specific sites on the plasma membrane prior to exocytosis. In rat kidney cells, RalB is required for functional assembly of the exocyst and for localizing the exocyst to the leading edge of migrating cells. In human cancer cells, RalA is required to support anchorage-independent proliferation and RalB is required to suppress apoptosis. RalA has been shown to localize to the plasma membrane while RalB is localized to the intracellular vesicles. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTAD--------LDTPRNCErylnwahAFLVVYSVDSR 98
Cdd:cd04139   12 GKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQLNILDTAGqedyaairDNYFRSGE-------GFLLVFSITDM 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  99 QSFDSSSSYLELLALHAKETQrsIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHEAVREA 178
Cdd:cd04139   85 ESFTALAEFREQILRVKEDDN--VPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTR-ANVDKVFFDLVREI 161

                 ..
gi 767984381 179 RR 180
Cdd:cd04139  162 RQ 163

Ras homology family (Rho) of small guanosine triphosphatases (GTPases); Members of the Rho (Ras homology) family include RhoA, Cdc42, Rac, Rnd, Wrch1, RhoBTB, and Rop. There are 22 human Rho family members identified currently. These proteins are all involved in the reorganization of the actin cytoskeleton in response to external stimuli. They also have roles in cell transformation by Ras in cytokinesis, in focal adhesion formation and in the stimulation of stress-activated kinase. These various functions are controlled through distinct effector proteins and mediated through a GTP-binding/GTPase cycle involving three classes of regulating proteins: GAPs (GTPase-activating proteins), GEFs (guanine nucleotide exchange factors), and GDIs (guanine nucleotide dissociation inhibitors). Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins. Since crystal structures often lack C-terminal residues, this feature is not available for annotation in many of the CDs in the hierarchy.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRNCeRYLNwAHAFLVVYSVDSRQSFDS 103
Cdd:cd00157   12 GKTCLLISYTTNKFPTEYVPTVFDNYSANVTVDGKQVNLGLWDTAgqeEYDRLRPL-SYPQ-TDVFLLCFSVDSPSSFEN 89

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381 104 SSS--YLELlalhaKETQRSIPALLLGNKLDM-----------AQYRQVTKAEGVALAGRFGCL-FFEVSAcLDFEHVQH 169
Cdd:cd00157   90 VKTkwYPEI-----KHYCPNVPIILVGTKIDLrddgntlkkleKKQKPITPEEGEKLAKEIGAVkYMECSA-LTQEGLKE 163

                 ....*..
gi 767984381 170 VFHEAVR 176
Cdd:cd00157  164 VFDEAIR 170

Rho (Ras homology) subfamily of Ras-like small GTPases; Members of this subfamily of Ras-like small GTPases include Cdc42 and Rac, as well as Rho isoforms.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381    27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTA---DLDTPRNceryLNW--AHAFLVVYSVDSRQSF 101
Cdd:smart00174  10 GKTCLLIVYTTNAFPEDYVPTVFENYSADVEVDGKPVELGLWDTAgqeDYDRLRP----LSYpdTDVFLICFSVDSPASF 85

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381   102 DSSSS--YLELlalhaKETQRSIPALLLGNKLDMAQYRQ------------VTKAEGVALAGRFGCL-FFEVSAcLDFEH 166
Cdd:smart00174  86 ENVKEkwYPEV-----KHFCPNVPIILVGTKLDLRNDKStleelskkkqepVTYEQGQALAKRIGAVkYLECSA-LTQEG 159

                          170
                   ....*....|..
gi 767984381   167 VQHVFHEAVREA 178
Cdd:smart00174 160 VREVFEEAIRAA 171

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRfISEYDPNLEDTYSSEE-TVDHQPVHLRVMDTADLDTPRN-CERYLNWAHAFLVVYSVdsrqsfDSS 104
Cdd:PLN03118  26 GKSSLLVSFISSS-VEDLAPTIGVDFKIKQlTVGGKRLKLTIWDTAGQERFRTlTSSYYRNAQGIILVYDV------TRR 98

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767984381 105 SSYLELLALHAKE-----TQRSIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDfEHVQHVFHE 173
Cdd:PLN03118  99 ETFTNLSDVWGKEvelysTNQDCVKMLVGNKVDRESERDVSREEGMALAKEHGCLFLECSAKTR-ENVEQCFEE 171

Rab GTPase family 2 (Rab2); Rab2 is localized on cis-Golgi membranes and interacts with Golgi matrix proteins. Rab2 is also implicated in the maturation of vesicular tubular clusters (VTCs), which are microtubule-associated intermediates in transport between the ER and Golgi apparatus. In plants, Rab2 regulates vesicle trafficking between the ER and the Golgi bodies and is important to pollen tube growth. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEE-TVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVYSVDSRQSFDSS 104
Cdd:cd01866   16 GKSCLLLQFTDKRFQPVHDLTIGVEFGARMiTIDGKQIKLQIWDTAGQESFRSITRsYYRGAAGALLVYDITRRETFNHL 95

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 767984381 105 SSYLELLALHAKETqrsIPALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSA 160
Cdd:cd01866   96 TSWLEDARQHSNSN---MTIMLIGNKCDLESRREVSYEEGEAFAREHGLIFMETSA 148

Rab GTPase family 26 (Rab26); Rab26 subfamily. First identified in rat pancreatic acinar cells, Rab26 is believed to play a role in recruiting mature granules to the plasma membrane upon beta-adrenergic stimulation. Rab26 belongs to the Rab functional group III, which are considered key regulators of intracellular vesicle transport during exocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVK-----FLTKRFISEYDPNLEDTYSseeTVDHQPVHLRVMDTADLDTPRNCER-YLNWAHAFLVVYSVDSRQS 100
Cdd:cd04112   12 GKTCLLVRfkdgaFLAGSFIATVGIQFTNKVV---TVDGVKVKLQIWDTAGQERFRSVTHaYYRDAHALLLLYDVTNKSS 88

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767984381 101 FDSSSSYLELLALHAKETQRsipALLLGNKLDMAQYRQVTKAEGVALAGRFGCLFFEVSACLDFeHVQHVFHEAVRE 177
Cdd:cd04112   89 FDNIRAWLTEILEYAQSDVV---IMLLGNKADMSGERVVKREDGERLAKEYGVPFMETSAKTGL-NVELAFTAVAKE 161

Ras homolog family, member G (RhoG) of small guanosine triphosphatases (GTPases); RhoG is a GTPase with high sequence similarity to members of the Rac subfamily, including the regions involved in effector recognition and binding. However, RhoG does not bind to known Rac1 and Cdc42 effectors, including proteins containing a Cdc42/Rac interacting binding (CRIB) motif. Instead, RhoG interacts directly with Elmo, an upstream regulator of Rac1, in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1. The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Thus RhoG activates Rac1 through Elmo and Dock180 to control cell morphology. RhoG has also been shown to play a role in caveolar trafficking and has a novel role in signaling the neutrophil respiratory burst stimulated by G protein-coupled receptor (GPCR) agonists. Most Rho proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Rho proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  27 GKLSLTVKFLTKRFISEYDPNLEDTYSSEETVDHQPVHLRVMDTADLDTPRNCeRYLNW--AHAFLVVYSV-DSRQSFDS 103
Cdd:cd01875   15 GKTCLLICYTTNAFPKEYIPTVFDNYSAQTAVDGRTVSLNLWDTAGQEEYDRL-RTLSYpqTNVFIICFSIaSPSSYENV 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381 104 SSSYLELLALHAKetqrSIPALLLGNKLDMAQYRQV------------TKAEGVALAGRFGCL-FFEVSAcLDFEHVQHV 170
Cdd:cd01875   94 RHKWHPEVCHHCP----NVPILLVGTKKDLRNDADTlkklkeqgqapiTPQQGGALAKQIHAVkYLECSA-LNQDGVKEV 168

                 ....*.
gi 767984381 171 FHEAVR 176
Cdd:cd01875  169 FAEAVR 174

Rab GTPase family 27a (Rab27a); The Rab27a subfamily consists of Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4. Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy. When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767984381  61 QPVHLRVMDTADLDTPRN-CERYLNWAHAFLVVYSVDSRQSFDSSSSYLELLALHAKETQRSIpaLLLGNKLDMAQYRQV 139
Cdd:cd04127   61 FRVHLQLWDTAGQERFRSlTTAFFRDAMGFLLMFDLTSEQSFLNVRNWMSQLQAHAYCENPDI--VLIGNKADLPDQREV 138

                         90       100
                 ....*....|....*....|..
gi 767984381 140 TKAEGVALAGRFGCLFFEVSAC 161
Cdd:cd04127  139 SERQARELADKYGIPYFETSAA 160