CUE domain found in the C-terminal of toll-interacting protein (Tollip) and similar proteins; Tollip is a new component of the IL-1RI pathway which contains an N-terminal C2 domain and a C-terminal CUE domain. Tollip binds to the cytoplasmic TIR domain of IL-1Rs after IL-1 stimulation. It is sufficient for recruitment of IRAK to IL-1Rs and negatively regulates IL-1-induced signaling by inhibiting IRAK phosphorylation. In addition, Tollip directly interacts with toll-like receptors TLR2 and TLR4, and plays an inhibitory role in TLR-mediated cell activation through suppressing phosphorylation and kinase activity of IRAK. Moreover, Tollip can associate with GAT domains of Tom1 and its related proteins Tom1L1 and Tom1L2, and facilitate the recruitment of clathrin onto endosomes.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 13591860 230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:cd14363   1 TEEDLKQIQEMFPNVDKEVIKSVLEANRGNKDAAINSLLQM 41

CUE domain found in the C-terminal of toll-interacting protein (Tollip) and similar proteins; Tollip is a new component of the IL-1RI pathway which contains an N-terminal C2 domain and a C-terminal CUE domain. Tollip binds to the cytoplasmic TIR domain of IL-1Rs after IL-1 stimulation. It is sufficient for recruitment of IRAK to IL-1Rs and negatively regulates IL-1-induced signaling by inhibiting IRAK phosphorylation. In addition, Tollip directly interacts with toll-like receptors TLR2 and TLR4, and plays an inhibitory role in TLR-mediated cell activation through suppressing phosphorylation and kinase activity of IRAK. Moreover, Tollip can associate with GAT domains of Tom1 and its related proteins Tom1L1 and Tom1L2, and facilitate the recruitment of clathrin onto endosomes.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 13591860 230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:cd14363   1 TEEDLKQIQEMFPNVDKEVIKSVLEANRGNKDAAINSLLQM 41

Domain that may be involved in binding ubiquitin-conjugating enzymes (UBCs); CUE domains also occur in two protein of the IL-1 signal transduction pathway, tollip and TAB2. Ponting (Biochem. J.) "Proteins of the Endoplasmic reticulum" (in press)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 13591860    230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:smart00546   2 NDEALHDLKEMFPNLDEEVIEAVLEANTGNVEATINNLLEG 42

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860     54 RLSITVVQAK-LAKNYGMTRMDPYCRLRLGYA---VYETPTAHNGAkNPRWNKVIQCTV-PPGVDSFYLEIFDERAFSMD 128
Cdd:smart00239   1 TLTVKIISARnLPPKDKGGKSDPYVKVSLDGDpkeKKKTKVVKNTL-NPVWNETFEFEVpPPELAELEIEVYDKDRFGRD 79

                           90       100
                   ....*....|....*....|...
gi 13591860    129 DRIAWTHITIpESLKQGQVEDEW 151
Cdd:smart00239  80 DFIGQVTIPL-SDLLLGGRHEKL 101

CUE domain found in the C-terminal of toll-interacting protein (Tollip) and similar proteins; Tollip is a new component of the IL-1RI pathway which contains an N-terminal C2 domain and a C-terminal CUE domain. Tollip binds to the cytoplasmic TIR domain of IL-1Rs after IL-1 stimulation. It is sufficient for recruitment of IRAK to IL-1Rs and negatively regulates IL-1-induced signaling by inhibiting IRAK phosphorylation. In addition, Tollip directly interacts with toll-like receptors TLR2 and TLR4, and plays an inhibitory role in TLR-mediated cell activation through suppressing phosphorylation and kinase activity of IRAK. Moreover, Tollip can associate with GAT domains of Tom1 and its related proteins Tom1L1 and Tom1L2, and facilitate the recruitment of clathrin onto endosomes.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 13591860 230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:cd14363   1 TEEDLKQIQEMFPNVDKEVIKSVLEANRGNKDAAINSLLQM 41

C2 domain; The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  55 LSITVVQAK-LAKNYGMTRMDPYCRLRLGYA-VYETPTAHNGaKNPRWNKVIQCTV-PPGVDSFYLEIFDERAFSMDDRI 131
Cdd:cd00030   1 LRVTVIEARnLPAKDLNGKSDPYVKVSLGGKqKFKTKVVKNT-LNPVWNETFEFPVlDPESDTLTVEVWDKDRFSKDDFL 79

                        90       100
                ....*....|....*....|...
gi 13591860 132 AWTHITIPESLKQGQVEDEWYSL 154
Cdd:cd00030  80 GEVEIPLSELLDSGKEGELWLPL 102

CUE domain; CUE domains have been shown to bind ubiquitin. It has been suggested that CUE domains are related to pfam00627 and this has been confirmed by the structure of the domain. CUE domains also occur in two protein of the IL-1 signal transduction pathway, tollip and TAB2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 13591860   230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:pfam02845   1 NEQMLETLKEMFPDLDEEVIRAVLEASNGNVEAAINALLEG 41

CUE domain found in ubiquitin-binding CUE proteins; This family includes many coupling of ubiquitin conjugation to endoplasmic reticulum degradation (CUE) domain containing proteins that are characterized by an FP and a di-leucine-like sequence and bind to monoubiquitin with varying affinities. Some higher eukaryotic CUE domain proteins do not bind monoubiquitin efficiently, since they carry LP, rather than FP among CUE domains. CUE domains form three-helix bundle structures and are distantly related to the ubiquitin-associated (UBA) domains which are widely occurring ubiquitin-binding motifs found in a broad range of cellular proteins in species ranging from yeast to human. The majority of family members contain one CUE domain, but some family members from fungi harbor two CUE domains.

                        10        20        30
                ....*....|....*....|....*....|....*...
gi 13591860 231 EEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLL 268
Cdd:cd14279   1 DEKLEQLQEMFPDLDEEVLEDVLEANNGDVEAAIDALL 38

C2 domain first and third repeat in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains either the first or third repeat in Synaptotagmin-like proteins with a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  53 GRLSITVVQAK--LAKNYGMTRM-----DPYCRLRLGYAVYETPTAHNGAkNPRWNKVIQCTVP--PGVdSFYLEIFDER 123
Cdd:cd08391   1 GVLRIHVIEAQdlVAKDKFVGGLvkgksDPYVIVRVGAQTFKSKVIKENL-NPKWNEVYEAVVDevPGQ-ELEIELFDED 78

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 13591860 124 AFSmDDRIAWTHITIPESLKQGQVeDEWYSLSgrqgDDKEGMINLVMS 171
Cdd:cd08391  79 PDK-DDFLGRLSIDLGSVEKKGFI-DEWLPLE----DVKSGRLHLKLE 120

CUE domain found in vacuolar protein sorting-associated protein 9 (VPS9) and similar proteins; VPS9, also called vacuolar protein-targeting protein 9, is a cytosolic yeast protein required for localization of vacuolar proteins, such as the soluble vacuolar hydrolases CPY and PrA. It may bind and act as an effector of a rab GTPase and plays a role in vacuolar protein sorting (VPS) pathway. VPS9 contains a region called GBH domain that is related to mammalian Ras-binding proteins, Rin1 and JC265, and may negatively regulate Ras-mediated signaling in yeast Saccharomyces cerevisiae. This model corresponds to the N-terminal CUE domain that interacts specifically with monoubiquitin and regulates intramolecular monoubiquitylation.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 13591860 230 NEEDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:cd14369   2 HKETLNTLQEMFPDLDKEIIKDVVIAKKGRIGECVDACLQL 42

C2 domain present in Soybean genes Regulated by Cold 2 (SRC2)-like proteins; SRC2 production is a response to pathogen infiltration. The initial response of increased Ca2+ concentrations are coupled to downstream signal transduction pathways via calcium binding proteins. SRC2 contains a single C2 domain which localizes to the plasma membrane and is involved in Ca2+ dependent protein binding. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  55 LSITVVQAK-LAKNYGMTRMDPYCRLRL-GYAVYETPTAHNGAKNPRWNKVIQCTVPPGVDSF-----YLEIFDERAFSM 127
Cdd:cd04051   2 LEITIISAEdLKNVNLFGKMKVYAVVWIdPSHKQSTPVDRDGGTNPTWNETLRFPLDERLLQQgrlalTIEVYCERPSLG 81

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 13591860 128 DDRIAWTHITIPESLKQGQVEDE----WYSLSGRQGDDKeGMINL 168
Cdd:cd04051  82 DKLIGEVRVPLKDLLDGASPAGElrflSYQLRRPSGKPQ-GVLNF 125

C2 domain first repeat present in Synaptotagmin-like proteins; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  53 GRLSITVVQAK-LAKN--YGMTRMDPYCRLRLGYAVYETPTAHNGAkNPRWNkvIQCTVP---PGVDSFYLEIFDERAFS 126
Cdd:cd04024   1 GVLRVHVVEAKdLAAKdrSGKGKSDPYAILSVGAQRFKTQTIPNTL-NPKWN--YWCEFPifsAQNQLLKLILWDKDRFA 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 13591860 127 MDDRIAWTHITIPESLKQGQVE--DEWYSL-SGRQGDD--KEGMINLVMS 171
Cdd:cd04024  78 GKDYLGEFDIALEEVFADGKTGqsDKWITLkSTRPGKTsvVSGEIHLQFS 127

CUE2 domain found in yeast ubiquitin-binding protein CUE2 (Cue2p) and similar proteins; Cue2p, also called coupling of ubiquitin conjugation to ER degradation protein 2, is encoded by the open reading frame (ORF) YKL090W. It is involved in the intramolecular monoubiquitination that serves as a regulatory signal in a variety of cellular processes in yeast. Cue2p contains two tandem CUE domains at the N-terminus. Both of them can bind monoubiquitin independently. This model corresponds to the second CUE domain.

                        10        20        30
                ....*....|....*....|....*....|....*..
gi 13591860 232 EDLKAIQDMFPNMDREVIRSVLEAQRGNKDAAINSLL 268
Cdd:cd14375   2 NDLDELKDMFPNLDSEVIEDCYVLCEKNVERTVSALL 38

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating protein which regulates the ADP ribosylation factor Arf, a member of the Ras superfamily of GTP-binding proteins. The GTP-bound form of Arf is involved in Golgi morphology and is involved in recruiting coat proteins. ArfGAP is responsible for the GDP-bound form of Arf which is necessary for uncoating the membrane and allowing the Golgi to fuse with an acceptor compartment. These proteins contain an N-terminal ArfGAP domain containing the characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) and C-terminal C2 domain. C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 13591860  52 VGRLSITVVQA-KLAKNyGMTRMDPYCRLRLGYAVYETPTAHNGAkNPRWNKVIQCTVPPGVDSFYLEIFDERAFSMDD 129
Cdd:cd04038   1 LGLLKVRVVRGtNLAVR-DFTSSDPYVVLTLGNQKVKTRVIKKNL-NPVWNEELTLSVPNPMAPLKLEVFDKDTFSKDD 77

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. Both proteins contain two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  54 RLSITVVQAK-LAKNYGMTRMDPYCRLRLGYAVYETPTAHNgAKNPRWNKVIQCTVPPGVDS-FYLEIFDERAFSMDDRI 131
Cdd:cd04025   1 RLRCHVLEARdLAPKDRNGTSDPFVRVFYNGQTLETSVVKK-SCYPRWNEVFEFELMEGADSpLSVEVWDWDLVSKNDFL 79

                        90       100       110
                ....*....|....*....|....*....|....*
gi 13591860 132 AWTHITIpESLKQGQVEDEWYSLS--GRQGDDKEG 164
Cdd:cd04025  80 GKVVFSI-QTLQQAKQEEGWFRLLpdPRAEEESGG 113

C2 domain present in the Human neural precursor cell-expressed, developmentally down-regulated 4 (NEDD4) and NEDD4-like (NEDD4L/NEDD42); Nedd4 and Nedd4-2 are two of the nine members of the Human Nedd4 family. All vertebrates appear to have both Nedd4 and Nedd4-2 genes. They are thought to participate in the regulation of epithelial Na+ channel (ENaC) activity. They also have identical specificity for ubiquitin conjugating enzymes (E2). Nedd4 and Nedd4-2 are composed of a C2 domain, 2-4 WW domains, and a ubiquitin ligase Hect domain. Their WW domains can bind PPxY (PY) or LPSY motifs, and in vitro studies suggest that WW3 and WW4 of both proteins bind PY motifs in the key substrates, with WW3 generally exhibiting higher affinity. Most Nedd4 family members, especially Nedd4-2, also have multiple splice variants, which might play different roles in regulating their substrates. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  55 LSITVVQA-KLAKN--YGMTrmDPYCRLRLgyavYETPTAHNGAK----------NPRWNKVIQCTVPPGVDSFYLEIFD 121
Cdd:cd04033   2 LRVKVLAGiDLAKKdiFGAS--DPYVKISL----YDPDGNGEIDSvqtktikktlNPKWNEEFFFRVNPREHRLLFEVFD 75

                        90       100       110
                ....*....|....*....|....*....|..
gi 13591860 122 ERAFSMDDRIAWTHITIPESLKQGQVEDEWYS 153
Cdd:cd04033  76 ENRLTRDDFLGQVEVPLNNLPTETPGNERRYT 107

CUE domain found in NEDD4-binding protein 2 (N4BP2) and similar proteins; N4BP2 has been identified as an oncogene bcl-3 coding protein BCL-3-binding protein (B3BP) that participates in connecting transcriptional activation and genetic recombination of the Ig gene. In addition to BCL-3, it also interacts with p300/CBP histone acetyltransferases. N4BP2 shows intrinsic ATP binding and hydrolyzing activity. It contains an N-terminal ATP-binding region that is responsible for the interaction with BCL-3 and p300/CBP. N4BP2 also functions as a 5'-polynucleotide kinase that can transfer a phosphate group to the 5' end of DNA and RNA substrates. Moreover, N4BP2 contains a C-terminal MutS-related domain that possesses nicking endonuclease activity and may play a role in DNA mismatch repair (MMR). This model corresponds to CUE domain in the N-terminus of N4BP2.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|.
gi 13591860 231 EEDLKAIQDMFP-NMDREVIRSVLEAQRGNKDAAINSLLQM 270
Cdd:cd14365   2 EELFQQLQEMFSgKLDPSVVYMVLSECDFKVDNAMDTLLNL 42

C2 domain first repeat; fungal group; C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 13591860  74 DPYCRL---RLGYAVYETPTAHNgAKNPRWNK--VIqCTVPPGVDS---FYLEIFDERAFSMDDRIAWTHITIPESLKQG 145
Cdd:cd04041  24 DPYVTAsfaKFGKPLYSTRIIRK-DLNPVWEEtwFV-LVTPDEVKAgerLSCRLWDSDRFTADDRLGRVEIDLKELIEDR 101

                .
gi 13591860 146 Q 146
Cdd:cd04041 102 N 102

C2 domain third repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); MCTPs are involved in Ca2+ signaling at the membrane. The cds in this family contain multiple C2 domains as well as a C-terminal PRT domain. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the third C2 repeat, C2C, and has a type-II topology.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 13591860  53 GRLSITVVQAK--LAKNYGmTRMDPYCRLRLGYAVYETPTAHNGAkNPRWNKVIQCTVPPGVDSFYLEIFDE 122
Cdd:cd08377   1 GFLQVKVIRASglAAADIG-GKSDPFCVLELVNARLQTHTIYKTL-NPEWNKIFTFPIKDIHDVLEVTVYDE 70

CUE domain found in activating signal cointegrator 1 complex subunit 2 (ASCC2) and similar proteins; ASCC2, also called ASC-1 complex subunit p100 or Trip4 complex subunit p100, together with ASCC1 (also called p50) and ASCC3 (also called p300), form the activating signal cointegrator complex (ASCC). ASCC plays an essential role in activating protein 1 (AP-1), serum response factor (SRF), and nuclear factor kappaB (NF-kappaB) transactivation. It acts as a transcriptional coactivator of nuclear receptors and regulates the transrepression between nuclear receptors and either AP-1 or NF-kappaB in vivo. Members in this family all contain a CUE domain.

                        10        20        30
                ....*....|....*....|....*....|..
gi 13591860 237 IQDMFPNMDREVIRSVLEAQRGNKDAAINSLL 268
Cdd:cd14364   7 VKDILPDLGEGFIEACLEHYNGNVERVINALL 38