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 50657357     34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvhenglscNEQL----NRCIRW 109
Cdd:smart00173   2 KLVVLGSGGVGKSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTAG----------QEEFsamrDQYMRT 71

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357    110 ADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdV 189
Cdd:smart00173  72 GEGFLLVYSITDRQSFEEIKKFREQILRVKDRDDVPIVLVGNKCDLESERVVSTEEGKELARQWGCPFLETSAKERVN-V 150

                          170
                   ....*....|.
gi 50657357    190 YSAFHVLCKEV 200
Cdd:smart00173 151 DEAFYDLVREI 161

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357   34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvHENGLSCNEQLnrcIRWADAV 113
Cdd:PTZ00369   7 KLVVVGGGGVGKSALTIQFIQNHFIDEYDPTIEDSYRKQCVIDEETCLLDILDTAG---QEEYSAMRDQY---MRTGQGF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357  114 VIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdVYSAF 193
Cdd:PTZ00369  81 LCVYSITSRSSFEEIASFREQILRVKDKDRVPMILVGNKCDLDSERQVSTGEGQELAKSFGIPFLETSAKQRVN-VDEAF 159

                        170       180
                 ....*....|....*....|.
gi 50657357  194 HVLCKEVSPKQQASGTPEKRR 214
Cdd:PTZ00369 160 YELVREIRKYLKEDMPSQKQK 180

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 50657357    33 VKIAVVGASGVGKTALVVRFL-TKRFIGDYERNAG-NLYTRQVHIEGETLAIQVQDTPGIQ-VHENGLSCNEQLNRCIRW 109
Cdd:TIGR00231   2 IKIVIVGHPNVGKSTLLNSLLgNKGSITEYYPGTTrNYVTTVIEEDGKTYKFNLLDTAGQEdYDAIRRLYYPQVERSLRV 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357   110 ADAVVIVFSITDHKS---YELISQLHQHVqqlhpgtrlPVVVVANKADLLHVKqVDPQLGLQLASMLGCSFYEVSVsENY 186
Cdd:TIGR00231  82 FDIVILVLDVEEILEkqtKEIIHHADSGV---------PIILVGNKIDLKDAD-LKTHVASEFAKLNGEPIIPLSA-ETG 150

                  ....*..
gi 50657357   187 NDVYSAF 193
Cdd:TIGR00231 151 KNIDSAF 157

Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases); The Ras family of the Ras superfamily includes classical N-Ras, H-Ras, and K-Ras, as well as R-Ras, Rap, Ral, Rheb, Rhes, ARHI, RERG, Rin/Rit, RSR1, RRP22, Ras2, Ras-dva, and RGK proteins. Ras proteins regulate cell growth, proliferation and differentiation. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These 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: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs 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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGIQVHenglscNEQLNRCIRWADAV 113
Cdd:cd00876   1 KLVVLGAGGVGKSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQEEF------SAMRDQYIRNGDGF 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 114 VIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdVYSAF 193
Cdd:cd00876  75 ILVYSITSRESFEEIKNIREQILRVKDKEDVPIVLVGNKCDLENERQVSTEEGEALAEEWGCPFLETSAKTNIN-IDELF 153

                ....*..
gi 50657357 194 HVLCKEV 200
Cdd:cd00876 154 NTLVREI 160

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 50657357     31 RLVKIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvhenglscNEQL----NRC 106
Cdd:smart00010   1 REYKLVVLGGGGVGKSALTIQFVQGHFVDEYDPTIEDSYRKQIEIDGEVCLLDILDTAG----------QEEFsamrDQY 70

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357    107 IRWADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENY 186
Cdd:smart00010  71 MRTGEGFLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGKELARQWGCPFLETSAKERI 150

                          170
                   ....*....|....
gi 50657357    187 NdVYSAFHVLCKEV 200
Cdd:smart00010 151 N-VDEAFYDLVREI 163

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 50657357  33 VKIAVVGASGVGKTALVVRFLTKRFIGDYERNAG-NLYTRQVHIEGETLAIQVQDTPGiQvhenglscnEQLnRCI---- 107
Cdd:cd00154   1 FKIVLIGDSGVGKTSLLLRFVDNKFSENYKSTIGvDFKSKTIEVDGKKVKLQIWDTAG-Q---------ERF-RSItssy 69

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 108 -RWADAVVIVFSITDHKSYELISQLHQHVQQLHPGTrLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENY 186
Cdd:cd00154  70 yRGAHGAILVYDVTNRESFENLDKWLNELKEYAPPN-IPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGE 148

                       170
                ....*....|..
gi 50657357 187 NdVYSAFHVLCK 198
Cdd:cd00154 149 N-VDEAFESLAR 159

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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvHENGLSCNEQLnrcIRWADAV 113
Cdd:cd04145   4 KLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAG---QEEFSAMREQY---MRTGEGF 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 114 VIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdVYSAF 193
Cdd:cd04145  78 LLVFSVTDRGSFEEVDKFHTQILRVKDRDEFPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETSAKDRVN-VDKAF 156

                ....*...
gi 50657357 194 HVLCKEVS 201
Cdd:cd04145 157 HDLVRVIR 164

Rab subfamily of small GTPases; Rab GTPases are implicated in vesicle trafficking.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357     33 VKIAVVGASGVGKTALVVRFLTKRFIGDYERNAG-NLYTRQVHIEGETLAIQVQDTPGiQvhenglscnEQLnRCI---- 107
Cdd:smart00175   1 FKIILIGDSGVGKSSLLSRFTDGKFSEQYKSTIGvDFKTKTIEVDGKRVKLQIWDTAG-Q---------ERF-RSItssy 69

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357    108 -RWADAVVIVFSITDHKSYE----LISQLHQHVQQlhpgtRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSV 182
Cdd:smart00175  70 yRGAVGALLVYDITNRESFEnlenWLKELREYASP-----NVVIMLVGNKSDLEEQRQVSREEAEAFAEEHGLPFFETSA 144

                          170
                   ....*....|....*...
gi 50657357    183 SENYNdVYSAFHVLCKEV 200
Cdd:smart00175 145 KTNTN-VEEAFEELAREI 161

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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvHENGLSCNEQLnrcIRWADAV 113
Cdd:cd04138   3 KLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAG---QEEYSAMRDQY---MRTGEGF 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 114 VIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADlLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdVYSAF 193
Cdd:cd04138  77 LCVFAINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCD-LAARTVSTRQGQDLAKSYGIPYIETSAKTRQG-VEEAF 154

                ....*..
gi 50657357 194 HVLCKEV 200
Cdd:cd04138 155 YTLVREI 161

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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIG-DYERNAGNLYTRQVHIEGETLAIQVQDTP----GIQVHENglscneqlnrCIR 108
Cdd:cd04148   2 RVVLLGDSGVGKSSLANIFTAGVYEDsAYEASGDDTYERTVSVDGEEATLVVYDHWeqedGMWLEDS----------CMQ 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 109 WADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNd 188
Cdd:cd04148  72 VGDAYVIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHN- 150

                       170       180       190       200
                ....*....|....*....|....*....|....*....|
gi 50657357 189 VYSAFHVLCKEV------SPKQQASGTPEKRRTSLIPRPK 222
Cdd:cd04148 151 VDELFEGIVRQVrlrrdsKEKNTRRMASRKRRESITKKAK 190

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 50657357  31 RLVKIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiQVHENGLscNEQLNRCirwA 110
Cdd:cd04141   1 REYKIVMLGAGGVGKSAVTMQFISHSFPDYHDPTIEDAYKTQARIDNEPALLDILDTAG-QAEFTAM--RDQYMRC---G 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 111 DAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYNdVY 190
Cdd:cd04141  75 EGFIICYSVTDRHSFQEASEFKELITRVRLTEDIPLVLVGNKVDLEQQRQVTTEEGRNLAREFNCPFFETSAALRFY-ID 153

                       170
                ....*....|....
gi 50657357 191 SAFHVLCKEVSPKQ 204
Cdd:cd04141 154 DAFHGLVREIRRKE 167

Rap2 family GTPase consists of Rap2a, Rap2b, and Rap2c; The Rap2 subgroup is part of the Rap subfamily of the Ras family. It consists of Rap2a, Rap2b, and Rap2c. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. 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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvhenglscNEQLNRC----IRW 109
Cdd:cd04176   3 KVVVLGSGGVGKSALTVQFVSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTAG----------TEQFASMrdlyIKN 72

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 50657357 110 ADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYN 187
Cdd:cd04176  73 GQGFIVVYSLVNQQTFQDIKPMRDQIVRVKGYEKVPIILVGNKVDLESEREVSSAEGRALAEEWGCPFMETSAKSKTM 150

Rap-like family consists of Rap1, Rap2 and RSR1; The Rap subfamily consists of the Rap1, Rap2, and RSR1. Rap subfamily proteins perform different cellular functions, depending on the isoform and its subcellular localization. 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 microsomal membrane of the pancreatic acini, as well as in the endocytic compartment of skeletal muscle cells and fibroblasts. Rap1 localizes in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines. 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. Rap2 is involved in multiple functions, including activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton and activation of the Wnt/beta-catenin signaling pathway in embryonic Xenopus. A number of effector proteins for Rap2 have been identified, including isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK), and the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. RSR1 is the fungal homolog of Rap1 and Rap2. In budding yeasts, it is involved in selecting a site for bud growth, which directs the establishment of cell polarization. The Rho family GTPase Cdc42 and its GEF, Cdc24, then establish an axis of polarized growth. It is believed that Cdc42 interacts directly with RSR1 in vivo. In filamentous fungi such as Ashbya gossypii, RSR1 is a key regulator of polar growth in the hypha. 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 50657357  34 KIAVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGIqvhenglscnEQLNRC----IRW 109
Cdd:cd04136   3 KLVVLGSGGVGKSALTVQFVQGIFVDKYDPTIEDSYRKQIEVDCQQCMLEILDTAGT----------EQFTAMrdlyIKN 72

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 50657357 110 ADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLG-CSFYEVS 181
Cdd:cd04136  73 GQGFALVYSITAQQSFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVSKEEGQNLARQWGnCPFLETS 145

Rat sarcoma (Ras)-like superfamily of small guanosine triphosphatases (GTPases); Ras-like GTPase superfamily. The Ras-like superfamily of small GTPases consists of several families with an extremely high degree of structural and functional similarity. The Ras superfamily is divided into at least four families in eukaryotes: the Ras, Rho, Rab, and Sar1/Arf families. This superfamily also includes proteins like the GTP translation factors, Era-like GTPases, and G-alpha chain of the heterotrimeric G proteins. Members of the Ras superfamily regulate a wide variety of cellular functions: the Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. The GTP translation factor family regulates initiation, elongation, termination, and release in translation, and the Era-like GTPase family regulates cell division, sporulation, and DNA replication. Members of the Ras superfamily are identified by the GTP binding site, which is made up of five characteristic sequence motifs, and the switch I and switch II regions.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357  36 AVVGASGVGKTALvVRFLTKRFIGDYERNAG-----NLYTRQVHIEGETlaIQVQDTPGIqVHENGLSCNEQLNRCIRWA 110
Cdd:cd00882   1 VVVGRGGVGKSSL-LNALLGGEVGEVSDVPGttrdpDVYVKELDKGKVK--LVLVDTPGL-DEFGGLGREELARLLLRGA 76

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 50657357 111 DAVVIVFSITDHKSYELIsqLHQHVQQLHpGTRLPVVVVANKADLLHVKQVDPQLGLQ-LASMLGCSFYEVSVSENYN 187
Cdd:cd00882  77 DLILLVVDSTDRESEEDA--KLLILRRLR-KEGIPIILVGNKIDLLEEREVEELLRLEeLAKILGVPVFEVSAKTGEG 151

Rab GTPase family 1 includes the yeast homolog Ypt1; Rab1/Ypt1 subfamily. Rab1 is found in every eukaryote and is a key regulatory component for the transport of vesicles from the ER to the Golgi apparatus. Studies on mutations of Ypt1, the yeast homolog of Rab1, showed that this protein is necessary for the budding of vesicles of the ER as well as for their transport to, and fusion with, the Golgi apparatus. 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 50657357  32 LVKIAVVGASGVGKTALVVRFLTKRFIGDYERNAG-NLYTRQVHIEGETLAIQVQDTPGiqvhenglscNEQLnRCI--- 107
Cdd:cd01869   2 LFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGvDFKIRTIELDGKTVKLQIWDTAG----------QERF-RTItss 70

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 108 --RWADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPvVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSEN 185
Cdd:cd01869  71 yyRGAHGIIIVYDVTDQESFNNVKQWLQEIDRYASENVNK-LLVGNKCDLTDKKVVDYTEAKEFADELGIPFLETSAKNA 149

                       170
                ....*....|....*
gi 50657357 186 YNdVYSAFHVLCKEV 200
Cdd:cd01869 150 TN-VEEAFMTMAREI 163

Ras homolog enriched in striatum (Rhes) and activator of G-protein signaling 1 (Dexras1/AGS1); This subfamily includes Rhes (Ras homolog enriched in striatum) and Dexras1/AGS1 (activator of G-protein signaling 1). These proteins are homologous, but exhibit significant differences in tissue distribution and subcellular localization. Rhes is found primarily in the striatum of the brain, but is also expressed in other areas of the brain, such as the cerebral cortex, hippocampus, inferior colliculus, and cerebellum. Rhes expression is controlled by thyroid hormones. In rat PC12 cells, Rhes is farnesylated and localizes to the plasma membrane. Rhes binds and activates PI3K, and plays a role in coupling serpentine membrane receptors with heterotrimeric G-protein signaling. Rhes has recently been shown to be reduced under conditions of dopamine supersensitivity and may play a role in determining dopamine receptor sensitivity. Dexras1/AGS1 is a dexamethasone-induced Ras protein that is expressed primarily in the brain, with low expression levels in other tissues. Dexras1 localizes primarily to the cytoplasm, and is a critical regulator of the circadian master clock to photic and nonphotic input. 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 50657357  30 RRLVkiaVVGASGVGKTALVVRFLTKRFIGDYERNAGNLYTRQVHIEGETLAIQVQDTPGiqvhENGLSCNEQLNrcIRW 109
Cdd:cd04143   1 YRMV---VLGASKVGKTAIVSRFLGGRFEEQYTPTIEDFHRKLYSIRGEVYQLDILDTSG----NHPFPAMRRLS--ILT 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 110 ADAVVIVFSITDHKSYELISQLHQHV--------QQLHPGTRLPVVVVANKADLLHVKQVD-PQLGLQLASMLGCSFYEV 180
Cdd:cd04143  72 GDVFILVFSLDNRESFEEVCRLREQIletksclkNKTKENVKIPMVICGNKADRDFPREVQrDEVEQLVGGDENCAYFEV 151

                       170
                ....*....|....*.
gi 50657357 181 SVSENYNdVYSAFHVL 196
Cdd:cd04143 152 SAKKNSN-LDEMFRAL 166

Rab GTPase family 23 (Rab23)-like; Rab23-like subfamily. Rab23 is a member of the Rab family of small GTPases. In mouse, Rab23 has been shown to function as a negative regulator in the sonic hedgehog (Shh) signaling pathway. Rab23 mediates the activity of Gli2 and Gli3, transcription factors that regulate Shh signaling in the spinal cord, primarily by preventing Gli2 activation in the absence of Shh ligand. Rab23 also regulates a step in the cytoplasmic signal transduction pathway that mediates the effect of Smoothened (one of two integral membrane proteins that are essential components of the Shh signaling pathway in vertebrates). In humans, Rab23 is expressed in the retina. Mice contain an isoform that shares 93% sequence identity with the human Rab23 and an alternative splicing isoform that is specific to the brain. This isoform causes the murine open brain phenotype, indicating it may have a role in the development of the central nervous system. 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 50657357  33 VKIAVVGASGVGKTALVVRFLTKRFIGDYERNAG-NLYTRQVHIE--GETLAIQVQDTPGIQVHenglscNEQLNRCIRW 109
Cdd:cd04106   1 IKVIVVGNGNVGKSSMIQRFVKGIFTKDYKKTIGvDFLEKQIFLRqsDEDVRLMLWDTAGQEEF------DAITKAYYRG 74

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 50657357 110 ADAVVIVFSITDHKSYELISQLHQHVQQLhpGTRLPVVVVANKADLLHVKQVDPQLGLQLASMLGCSFYEVSVSENYN 187
Cdd:cd04106  75 AQACILVFSTTDRESFEAIESWKEKVEAE--CGDIPMVLVQTKIDLLDQAVITNEEAEALAKRLQLPLFRTSVKDDFN 150

Centaurin gamma (CENTG) GTPase; The centaurins (alpha, beta, gamma, and delta) are large, multi-domain proteins that all contain an ArfGAP domain and ankyrin repeats, and in some cases, numerous additional domains. Centaurin gamma contains an additional GTPase domain near its N-terminus. The specific function of this GTPase domain has not been well characterized, but centaurin gamma 2 (CENTG2) may play a role in the development of autism. Centaurin gamma 1 is also called PIKE (phosphatidyl inositol (PI) 3-kinase enhancer) and centaurin gamma 2 is also known as AGAP (ArfGAP protein with a GTPase-like domain, ankyrin repeats and a Pleckstrin homology domain) or GGAP. Three isoforms of PIKE have been identified. PIKE-S (short) and PIKE-L (long) are brain-specific isoforms, with PIKE-S restricted to the nucleus and PIKE-L found in multiple cellular compartments. A third isoform, PIKE-A was identified in human glioblastoma brain cancers and has been found in various tissues. GGAP has been shown to have high GTPase activity due to a direct intramolecular interaction between the N-terminal GTPase domain and the C-terminal ArfGAP domain. In human tissue, AGAP mRNA was detected in skeletal muscle, kidney, placenta, brain, heart, colon, and lung. Reduced expression levels were also observed in the spleen, liver, and small intestine.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357  33 VKIAVVGASGVGKTALVVRFLTKRFIGDyERNAGNLYTRQVHIEGETLAIQVQD---TPGIQVHEnglscneqlnrcirW 109
Cdd:cd04103   1 LKLGIVGNLRSGKSALVHRYLTGSYVQL-ESPEGGRFKKEVLVDGQSHLLLIRDeggAPDAQFAG--------------W 65

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 50657357 110 ADAVVIVFSITDHKSYELISQLHQHVQQLHPGTRLPVVVVANKaDLLHVKQ---VDPQLGLQLAS-MLGCSFYEVSVSEN 185
Cdd:cd04103  66 VDAVIFVFSLEDEASFQTVYRLYHQLSSYRNISEIPLILVGTQ-DAISASNprvIDDARARQLCAdMKRCSYYETCATYG 144

                       170
                ....*....|....*
gi 50657357 186 YNdVYSAFHVLCKEV 200
Cdd:cd04103 145 LN-VERVFQEAAQKI 158