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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYI-CAYDLSLDDdYGQKTVSVlvDNIETDLEIIDHPACE--MSTEAFCATyNIDLF 1065
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTAGVYEdSAYEASGDD-TYERTVSV--DGEEATLVVYDHWEQEdgMWLEDSCMQ-VGDAY 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1066 VVVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLV 1145
Cdd:cd04148    77 VIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFE 156

                         170
                  ....*....|.
gi 442615115 1146 GIVAQVKLNPQ 1156
Cdd:cd04148   157 GIVRQVRLRRD 167

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYI-CAYDLSLDDdYGQKTVSVlvDNIETDLEIIDHPACE--MSTEAFCATyNIDLF 1065
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTAGVYEdSAYEASGDD-TYERTVSV--DGEEATLVVYDHWEQEdgMWLEDSCMQ-VGDAY 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1066 VVVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLV 1145
Cdd:cd04148    77 VIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFE 156

                         170
                  ....*....|.
gi 442615115 1146 GIVAQVKLNPQ 1156
Cdd:cd04148   157 GIVRQVRLRRD 167

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 442615115   990 KIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVSVlvDNIETDLEIIDhpacemsT------EAFCATY--N 1061
Cdd:pfam00071    1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTIGVDFYTKTIEV--DGKTVKLQIWD-------TagqerfRALRPLYyrG 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  1062 IDLFVVVYSVIDRNTFaaaERVLQYLKENEMLLSRGA--ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHN 1139
Cdd:pfam00071   72 ADGFLLVYDITSRDSF---ENVKKWVEEILRHADENVpiVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNEN 148

                          170
                   ....*....|...
gi 442615115  1140 VDELLVGIVAQVK 1152
Cdd:pfam00071  149 VEEAFEELAREIL 161

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 442615115   989 YKIAMLGASGVGKTTLTYQFT-TSDYICAYDLSLDDDYGqkTVSVLVDNIETDLEIIDHPACE----------MSTEAFC 1057
Cdd:TIGR00231    2 IKIVIVGHPNVGKSTLLNSLLgNKGSITEYYPGTTRNYV--TTVIEEDGKTYKFNLLDTAGQEdydairrlyyPQVERSL 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  1058 ATYNIDLFVVvysvidrntfAAAERVLQYLKENEMLLSRGA--ILVANKTDLqRHRVVTRQMGRKVAKEIACKFIETSSG 1135
Cdd:TIGR00231   80 RVFDIVILVL----------DVEEILEKQTKEIIHHADSGVpiILVGNKIDL-KDADLKTHVASEFAKLNGEPIIPLSAE 148

                   ....*...
gi 442615115  1136 LDHNVDEL 1143
Cdd:TIGR00231  149 TGKNIDSA 156

Amelogenins, cell adhesion proteins, play a role in the biomineralisation of teeth; They seem to regulate formation of crystallites during the secretory stage of tooth enamel development and are thought to play a major role in the structural organisation and mineralisation of developing enamel. The extracellular matrix of the developing enamel comprises two major classes of protein: the hydrophobic amelogenins and the acidic enamelins. Circular dichroism studies of porcine amelogenin have shown that the protein consists of 3 discrete folding units: the N-terminal region appears to contain beta-strand structures, while the C-terminal region displays characteristics of a random coil conformation. Subsequent studies on the bovine protein have indicated the amelogenin structure to contain a repetitive beta-turn segment and a "beta-spiral" between Gln112 and Leu138, which sequester a (Pro, Leu, Gln) rich region. The beta-spiral offers a probable site for interactions with Ca2+ ions. Muatations in the human amelogenin gene (AMGX) cause X-linked hypoplastic amelogenesis imperfecta, a disease characterised by defective enamel. A 9bp deletion in exon 2 of AMGX results in the loss of codons for Ile5, Leu6, Phe7 and Ala8, and replacement by a new threonine codon, disrupting the 16-residue (Met1-Ala16) amelogenin signal peptide.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115    458 QHPGGGVHQQHQVMVAHQAHAHT-QVSNQQPVL--QVQLPTPGVHVV-----HR-LLPTPPTHSGKGAYHTRETALQRVQ 528
Cdd:smart00818   36 HHQIIPVSQQHPPTHTLQPHHHIpVLPAQQPVVpqQPLMPVPGQHSMtptqhHQpNLPQPAQQPFQPQPLQPPQPQQPMQ 115

                    ...
gi 442615115    529 QQS 531
Cdd:smart00818  116 PQP 118

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYI-CAYDLSLDDdYGQKTVSVlvDNIETDLEIIDHPACE--MSTEAFCATyNIDLF 1065
Cdd:cd04148     1 YRVVLLGDSGVGKSSLANIFTAGVYEdSAYEASGDD-TYERTVSV--DGEEATLVVYDHWEQEdgMWLEDSCMQ-VGDAY 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1066 VVVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLV 1145
Cdd:cd04148    77 VIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFE 156

                         170
                  ....*....|.
gi 442615115 1146 GIVAQVKLNPQ 1156
Cdd:cd04148   157 GIVRQVRLRRD 167

Small GTPase of the Ras superfamily; ill-defined subfamily; SMART predicts Ras-like small GTPases of the ARF, RAB, RAN, RAS, and SAR subfamilies. Others that could not be classified in this way are predicted to be members of the small GTPase superfamily without predictions of the subfamily.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115    989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVsvlVDNIETDLEIIDhpacEMSTEAFCA---TY--NID 1063
Cdd:smart00010    3 YKLVVLGGGGVGKSALTIQFVQGHFVDEYDPTIEDSYRKQIE---IDGEVCLLDILD----TAGQEEFSAmrdQYmrTGE 75

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115   1064 LFVVVYSVIDRNTFAAAERVLQYL---KENE---MllsrgaILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLD 1137
Cdd:smart00010   76 GFLLVYSITDRQSFEEIAKFREQIlrvKDRDdvpI------VLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKER 149

                           170
                    ....*....|....*
gi 442615115   1138 HNVDELLVGIVAQVK 1152
Cdd:smart00010  150 INVDEAFYDLVREIR 164

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 442615115   990 KIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVSVlvDNIETDLEIIDhpacemsT------EAFCATY--N 1061
Cdd:pfam00071    1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTIGVDFYTKTIEV--DGKTVKLQIWD-------TagqerfRALRPLYyrG 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  1062 IDLFVVVYSVIDRNTFaaaERVLQYLKENEMLLSRGA--ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHN 1139
Cdd:pfam00071   72 ADGFLLVYDITSRDSF---ENVKKWVEEILRHADENVpiVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNEN 148

                          170
                   ....*....|...
gi 442615115  1140 VDELLVGIVAQVK 1152
Cdd:pfam00071  149 VEEAFEELAREIL 161

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 442615115  990 KIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYgqkTVSVLVDNIETDLEIIDHPACEMSTEAFCATYNI---DLFV 1066
Cdd:cd04146     1 KIAVLGASGVGKSALTVRFLTKRFIGEYEPNLESLY---SRQVTIDGEQVSLEIQDTPGQQQNEDPESLERSLrwaDGFV 77

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 442615115 1067 VVYSVIDRNTFAAAERVLQYLKENEMLLSRGA-ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHN 1139
Cdd:cd04146    78 LVYSITDRSSFDVVSQLLQLIREIKKRDGEIPvILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAAENYL 151

Ras-related in brain (Rab) family of small guanosine triphosphatases (GTPases); Rab GTPases form the largest family within the Ras superfamily. There are at least 60 Rab genes in the human genome, and a number of Rab GTPases are conserved from yeast to humans. Rab GTPases are small, monomeric proteins that function as molecular switches to regulate vesicle trafficking pathways. The different Rab GTPases are localized to the cytosolic face of specific intracellular membranes, where they regulate distinct steps in membrane traffic pathways. In the GTP-bound form, Rab GTPases recruit specific sets of effector proteins onto membranes. Through their effectors, Rab GTPases regulate vesicle formation, actin- and tubulin-dependent vesicle movement, and membrane fusion. 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 mask C-terminal lipid binding and promote cytosolic localization. While most unicellular organisms possess 5-20 Rab members, several have been found to possess 60 or more Rabs; for many of these Rab isoforms, homologous proteins are not found in other organisms. 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. Since crystal structures often lack C-terminal residues, the lipid modification site is not available for annotation in many of the CDs in the hierarchy, but is included where possible.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVSVlvDNIETDLEIIDhpacemsT---EAFCA---TY-- 1060
Cdd:cd00154     1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTIGVDFKSKTIEV--DGKKVKLQIWD-------TagqERFRSitsSYyr 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1061 NIDLFVVVYSVIDRNTFaaaERVLQYLKENEMLLSRGA--ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDH 1138
Cdd:cd00154    72 GAHGAILVYDVTNRESF---ENLDKWLNELKEYAPPNIpiILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGE 148

                         170
                  ....*....|
gi 442615115 1139 NVDELLVGIV 1148
Cdd:cd00154   149 NVDEAFESLA 158

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKtvsVLVDNIETDLEIIDhpacEMSTEAFCATYNIDL---- 1064
Cdd:cd04175     2 YKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQ---VEVDGQQCMLEILD----TAGTEQFTAMRDLYMkngq 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1065 -FVVVYSVIDRNTFAAaervLQYLKEnEMLLSRGA-----ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDH 1138
Cdd:cd04175    75 gFVLVYSITAQSTFND----LQDLRE-QILRVKDTedvpmILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSAKAKI 149

                         170
                  ....*....|...
gi 442615115 1139 NVDELLVGIVAQV 1151
Cdd:cd04175   150 NVNEIFYDLVRQI 162

Rat sarcoma (Ras) family 2 of small guanosine triphosphatases (GTPases); The Ras2 subfamily, found exclusively in fungi, was first identified in Ustilago maydis. In U. maydis, Ras2 is regulated by Sql2, a protein that is homologous to GEFs (guanine nucleotide exchange factors) of the CDC25 family. Ras2 has been shown to induce filamentous growth, but the signaling cascade through which Ras2 and Sql2 regulate cell morphology is not known. 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 442615115  990 KIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVsvlVDNIETDLEIIDHPACEMSTeAFCATYNIDL--FVV 1067
Cdd:cd04144     1 KLVVLGDGGVGKTALTIQLCLNHFVETYDPTIEDSYRKQVV---VDGQPCMLEVLDTAGQEEYT-ALRDQWIREGegFIL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1068 VYSVIDRNTFAAAERVLQYLKENEMLLSRGAI--LVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLV 1145
Cdd:cd04144    77 VYSITSRSTFERVERFREQIQRVKDESAADVPimIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNVNVERAFY 156

                         170
                  ....*....|.
gi 442615115 1146 GIVAQVKLNPQ 1156
Cdd:cd04144   157 TLVRALRQQRQ 167

Ras-like protein in all tissues (Rit), Ras-like protein in neurons (Rin) and Ras-related protein which interacts with calmodulin (Ric); Rit (Ras-like protein in all tissues), Rin (Ras-like protein in neurons) and Ric (Ras-related protein which interacts with calmodulin) form a subfamily with several unique structural and functional characteristics. These proteins all lack a the C-terminal CaaX lipid-binding motif typical of Ras family proteins, and Rin and Ric contain calmodulin-binding domains. Rin, which is expressed only in neurons, induces neurite outgrowth in rat pheochromocytoma cells through its association with calmodulin and its activation of endogenous Rac/cdc42. Rit, which is ubiquitously expressed in mammals, inhibits growth-factor withdrawl-mediated apoptosis and induces neurite extension in pheochromocytoma cells. Rit and Rin are both able to form a ternary complex with PAR6, a cell polarity-regulating protein, and Rac/cdc42. This ternary complex is proposed to have physiological function in processes such as tumorigenesis. Activated Ric is likely to signal in parallel with the Ras pathway or stimulate the Ras pathway at some upstream point, and binding of calmodulin to Ric may negatively regulate Ric activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVsvlVDNIETDLEIIDhPACEMSTEAFCATYNI--DLFV 1066
Cdd:cd04141     3 YKIVMLGAGGVGKSAVTMQFISHSFPDYHDPTIEDAYKTQAR---IDNEPALLDILD-TAGQAEFTAMRDQYMRcgEGFI 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1067 VVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLVG 1146
Cdd:cd04141    79 ICYSVTDRHSFQEASEFKELITRVRLTEDIPLVLVGNKVDLEQQRQVTTEEGRNLAREFNCPFFETSAALRFYIDDAFHG 158

                  ....*.
gi 442615115 1147 IVAQVK 1152
Cdd:cd04141   159 LVREIR 164

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKtvsVLVDNIETDLEIIDhPACEMSTEAFCATY--NIDLFV 1066
Cdd:cd04138     2 YKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQ---VVIDGETCLLDILD-TAGQEEYSAMRDQYmrTGEGFL 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1067 VVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLqRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDELLVG 1146
Cdd:cd04138    78 CVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDL-AARTVSTRQGQDLAKSYGIPYIETSAKTRQGVEEAFYT 156

                  ....*.
gi 442615115 1147 IVAQVK 1152
Cdd:cd04138   157 LVREIR 162

Rab GTPase family 6 (Rab6); Rab6 is involved in microtubule-dependent transport pathways through the Golgi and from endosomes to the Golgi. Rab6A of mammals is implicated in retrograde transport through the Golgi stack, and is also required for a slow, COPI-independent, retrograde transport pathway from the Golgi to the endoplasmic reticulum (ER). This pathway may allow Golgi residents to be recycled through the ER for scrutiny by ER quality-control systems. Yeast Ypt6p, the homolog of the mammalian Rab6 GTPase, is not essential for cell viability. Ypt6p acts in endosome-to-Golgi, in intra-Golgi retrograde transport, and possibly also in Golgi-to-ER trafficking. 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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTvsVLVDNIETDLEIIDhPACEMSTEAFCATYNIDLF--V 1066
Cdd:cd01861     1 HKLVFLGDQSVGKTSIITRFMYDTFDNQYQATIGIDFLSKT--MYVDDKTVRLQLWD-TAGQERFRSLIPSYIRDSSvaV 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1067 VVYSVIDRNTFAAAERVLQYLKENemllsRGA----ILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDE 1142
Cdd:cd01861    78 VVYDITNRQSFDNTDKWIDDVRDE-----RGNdviiVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSAKAGHNVKQ 152

                  .
gi 442615115 1143 L 1143
Cdd:cd01861   153 L 153

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKtvsVLVDNIETDLEIID------HPACEMSTEAFCatyni 1062
Cdd:cd04139     1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKK---VVLDGEEVQLNILDtagqedYAAIRDNYFRSG----- 72

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1063 DLFVVVYSVIDRNTFAAA----ERVLQYLKENEMLLsrgaILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDH 1138
Cdd:cd04139    73 EGFLLVFSITDMESFTALaefrEQILRVKEDDNVPL----LLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRA 148

                         170
                  ....*....|....
gi 442615115 1139 NVDELLVGIVAQVK 1152
Cdd:cd04139   149 NVDKVFFDLVREIR 162

Rab-related GTPase family includes Rab5 and Rab22; regulates early endosome fusion; The Rab5-related subfamily includes Rab5 and Rab22 of mammals, Ypt51/Ypt52/Ypt53 of yeast, and RabF of plants. The members of this subfamily are involved in endocytosis and endocytic-sorting pathways. In mammals, Rab5 GTPases localize to early endosomes and regulate fusion of clathrin-coated vesicles to early endosomes and fusion between early endosomes. In yeast, Ypt51p family members similarly regulate membrane trafficking through prevacuolar compartments. 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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYicaydlsldDDYGQKTV-------SVLVDNIETDLEIID-------HPACEMSTE 1054
Cdd:cd01860     2 FKLVLLGDSSVGKSSIVLRFVKNEF---------SENQESTIgaafltqTVNLDDTTVKFEIWDtagqeryRSLAPMYYR 72

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1055 -AFCAtynidlfVVVYSVIDRNTFAAAERVLQYLKEN---EMLLsrgaILVANKTDLQRHRVVTRQMGRKVAKEIACKFI 1130
Cdd:cd01860    73 gAAAA-------IVVYDITSEESFEKAKSWVKELQEHgppNIVI----ALAGNKADLESKRQVSTEEAQEYADENGLLFM 141

                         170
                  ....*....|....*..
gi 442615115 1131 ETSSGLDHNVDELLVGI 1147
Cdd:cd01860   142 ETSAKTGENVNELFTEI 158

A Ras homolog member I (ARHI); ARHI (A Ras homolog member I) is a member of the Ras family with several unique structural and functional properties. ARHI is expressed in normal human ovarian and breast tissue, but its expression is decreased or eliminated in breast and ovarian cancer. ARHI contains an N-terminal extension of 34 residues (human) that is required to retain its tumor suppressive activity. Unlike most other Ras family members, ARHI is maintained in the constitutively active (GTP-bound) state in resting cells and has modest GTPase activity. ARHI inhibits STAT3 (signal transducers and activators of transcription 3), a latent transcription factor whose abnormal activation plays a critical role in oncogenesis. 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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQktvSVLVDNIETDLEIIDhpacEMSTEAFCATYNIDL---- 1064
Cdd:cd04140     2 YRVVVFGAGGVGKSSLVLRFVKGTFRESYIPTIEDTYRQ---VISCSKSICTLQITD----TTGSHQFPAMQRLSIskgh 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1065 -FVVVYSVIDRNTFAAAERVLQYLKE--NEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVD 1141
Cdd:cd04140    75 aFILVYSITSKQSLEELKPIYELICEikGNNLEKIPIMLVGNKCDESPSREVSSSEGAALARTWNCAFMETSAKTNHNVQ 154

                  ..
gi 442615115 1142 EL 1143
Cdd:cd04140   155 EL 156

Rab family protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICAYDLSLDDDYGQKTVSVlvDNIETDLEIIDhPACEMSTEAFCATY--NIDLFV 1066
Cdd:PLN03108    7 FKYIIIGDTGVGKSCLLLQFTDKRFQPVHDLTIGVEFGARMITI--DNKPIKLQIWD-TAGQESFRSITRSYyrGAAGAL 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1067 VVYSVIDRNTF----AAAERVLQYLKENEMLLsrgaiLVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDE 1142
Cdd:PLN03108   84 LVYDITRRETFnhlaSWLEDARQHANANMTIM-----LIGNKCDLAHRRAVSTEEGEQFAKEHGLIFMEASAKTAQNVEE 158

                         170
                  ....*....|....
gi 442615115 1143 LLVGIVAQVKLNPQ 1156
Cdd:PLN03108  159 AFIKTAAKIYKKIQ 172

Rab GTPase-like family 4 (Rab-like4); RabL4 (Rab-like4) subfamily. RabL4s are novel proteins that have high sequence similarity with Rab family members, but display features that are distinct from Rabs, and have been termed Rab-like. As in other Rab-like proteins, RabL4 lacks a prenylation site at the C-terminus. The specific function of RabL4 remains unknown.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115  990 KIAMLGASGVGKTTLTyQFTTSD---YICAYDLSLDDDYGQKTVSVLVDNIETDLEIIDHPACEMSTEAfCATY--NIDL 1064
Cdd:cd04101     2 QCAVVGDPAVGKSALV-QMFHSDgatFQKNYTMTTGCDLVVKTVPVPDTSDSVELFIFDSAGQELFSDM-VENVweQPAV 79

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1065 FVVVYSVIDRNTFAAAERVLQYLKENEMLLSRGAILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSS 1134
Cdd:cd04101    80 VCVVYDVTNEVSFNNCSRWINRVRTHSHGLHTPGVLVGNKCDLTDRREVDAAQAQALAQANTLKFYETSA 149

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 442615115  989 YKIAMLGASGVGKTTLTYQFTTSDYICA-YDLSLDDDYGQKTVSVlvDNIETDLEIIDHPACEMSTEAFCATY-NIDLFV 1066
Cdd:cd04112     1 FKVMLVGDSGVGKTCLLVRFKDGAFLAGsFIATVGIQFTNKVVTV--DGVKVKLQIWDTAGQERFRSVTHAYYrDAHALL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615115 1067 VVYSVIDRNTF----AAAERVLQYLKENEMLlsrgaILVANKTDLQRHRVVTRQMGRKVAKEIACKFIETSSGLDHNVDE 1142
Cdd:cd04112    79 LLYDVTNKSSFdnirAWLTEILEYAQSDVVI-----MLLGNKADMSGERVVKREDGERLAKEYGVPFMETSAKTGLNVEL 153