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 389628760   9 EYKLVVVGGGGVGKSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVY 88
Cdd:cd04138    1 EYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVF 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  89 SITSRQSFEEITTFQQQILRVKDKDYFPMVVVGNKCDLEGeREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVR 168
Cdd:cd04138   81 AINSRKSFEDIHTYREQIKRVKDSDDVPMVLVGNKCDLAA-RTVSTRQGQDLAKSYGIPYIETSAKTRQGVEEAFYTLVR 159

                 ...
gi 389628760 169 EIR 171
Cdd:cd04138  160 EIR 162

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 389628760   22 KSCLTIQLIQSHFVDEYDPTI-EDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:pfam00071  12 KSSLLIRFTQNKFPEEYIPTIgVDFYTKTIEVDGKTVKLQIWDTAGQERFRALRPLYYRGADGFLLVYDITSRDSFENVK 91

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 389628760  101 TFQQQILRVKDKDyFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIRR 172
Cdd:pfam00071  92 KWVEEILRHADEN-VPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVEEAFEELAREILK 162

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  19 GVGKSCLTIQLIQSHF-VDEYDPTIE-DSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEG---FLLVYSITSR 93
Cdd:COG1100   13 GVGKTSLVNRLVGDIFsLEKYLSTNGvTIDKKELKLDGLDVDLVIWDTPGQDEFRETRQFYARQLTGaslYLFVVDGTRE 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  94 QSFEEITTFQQQILRVKDKdyFPMVVVGNKCDLEGEREVTRQEG--EALARSFNCKFIETSAKSRINVDKAFYDIVREIR 171
Cdd:COG1100   93 ETLQSLYELLESLRRLGKK--SPIILVLNKIDLYDEEEIEDEERlkEALSEDNIVEVVATSAKTGEGVEELFAALAEILR 170

                 .
gi 389628760 172 R 172
Cdd:COG1100  171 G 171

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 389628760    22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEITT 101
Cdd:smart00173  13 KSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTAGQEEFSAMRDQYMRTGEGFLLVYSITDRQSFEEIKK 92

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 389628760   102 FQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIRRY 173
Cdd:smart00173  93 FREQILRVKDRDDVPIVLVGNKCDLESERVVSTEEGKELARQWGCPFLETSAKERVNVDEAFYDLVREIRKK 164

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 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEITT 101
Cdd:cd00876   12 KSALTIRFVSGEFVEEYDPTIEDSYRKQIVVDGETYTLDILDTAGQEEFSAMRDQYIRNGDGFILVYSITSRESFEEIKN 91

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 389628760 102 FQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREI 170
Cdd:cd00876   92 IREQILRVKDKEDVPIVLVGNKCDLENERQVSTEEGEALAEEWGCPFLETSAKTNINIDELFNTLVREI 160

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 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEITT 101
Cdd:cd04145   15 KSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAGQEEFSAMREQYMRTGEGFLLVFSVTDRGSFEEVDK 94

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 102 FQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIR 171
Cdd:cd04145   95 FHTQILRVKDRDEFPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETSAKDRVNVDKAFHDLVRVIR 164

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 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEITT 101
Cdd:cd04144   12 KTALTIQLCLNHFVETYDPTIEDSYRKQVVVDGQPCMLEVLDTAGQEEYTALRDQWIREGEGFILVYSITSRSTFERVER 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 102 FQQQILRVKDKDY--FPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIRrynREMQG 179
Cdd:cd04144   92 FREQIQRVKDESAadVPIMIVGNKCDKVYEREVSTEEGAALARRLGCEFIEASAKTNVNVERAFYTLVRALR---QQRQG 168

                        170       180       190
                 ....*....|....*....|....*....|....*
gi 389628760 180 ystgsGGSNAGGPSNKMEVNDsdaeagccSKCVLM 214
Cdd:cd04144  169 -----GQGPKGGPTKKKEKKK--------RKCVIM 190

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 389628760   9 EYKLVVVGGGGVGKSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVY 88
Cdd:cd04175    1 EYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAGTEQFTAMRDLYMKNGQGFVLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  89 SITSRQSFEEITTFQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVR 168
Cdd:cd04175   81 SITAQSTFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSAKAKINVNEIFYDLVR 160

                 ....
gi 389628760 169 EIRR 172
Cdd:cd04175  161 QINR 164

RSR1/Bud1p family GTPase; RSR1/Bud1p is a member of the Rap subfamily of the Ras family that is found in fungi. In budding yeasts, RSR1 is involved in selecting a site for bud growth on the cell cortex, which directs the establishment of cell polarization. The Rho family GTPase cdc42 and its GEF, cdc24, then establish an axis of polarized growth by organizing the actin cytoskeleton and secretory apparatus at the bud site. It is believed that cdc42 interacts directly with RSR1 in vivo. In filamentous fungi, polar growth occurs at the tips of hypha and at novel growth sites along the extending hypha. In Ashbya gossypii, RSR1 is a key regulator of hyphal growth, localizing at the tip region and regulating in apical polarization of the actin cytoskeleton. 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 389628760   9 EYKLVVVGGGGVGKSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVY 88
Cdd:cd04177    1 DYKIVVLGAGGVGKSALTVQFVQNVFIESYDPTIEDSYRKQVEIDGRQCDLEILDTAGTEQFTAMRELYIKSGQGFLLVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  89 SITSRQSFEEITTFQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFN-CKFIETSAKSRINVDKAFYDIV 167
Cdd:cd04177   81 SVTSEASLNELGELREQVLRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQWGnVPFYETSARKRTNVDEVFIDLV 160

                 ....
gi 389628760 168 REIR 171
Cdd:cd04177  161 RQII 164

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 389628760   9 EYKLVVVGGGGVGKSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVY 88
Cdd:cd04176    1 EYKVVVLGSGGVGKSALTVQFVSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTAGTEQFASMRDLYIKNGQGFIVVY 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  89 SITSRQSFEEITTFQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVR 168
Cdd:cd04176   81 SLVNQQTFQDIKPMRDQIVRVKGYEKVPIILVGNKVDLESEREVSSAEGRALAEEWGCPFMETSAKSKTMVNELFAEIVR 160

                 ..
gi 389628760 169 EI 170
Cdd:cd04176  161 QM 162

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 389628760  22 KSCLTIQLIQSHFVDEYDPTI-EDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:cd00154   13 KTSLLLRFVDNKFSENYKSTIgVDFKSKTIEVDGKKVKLQIWDTAGQERFRSITSSYYRGAHGAILVYDVTNRESFENLD 92

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 389628760 101 TFQQQILRVKDKDyFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVR 168
Cdd:cd00154   93 KWLNELKEYAPPN-IPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGENVDEAFESLAR 159

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 389628760  19 GVGKSCLTIQLIQSHFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSA--MREQYMRTGEGFLLVYSITSRQSF 96
Cdd:cd04146    9 GVGKSALTVRFLTKRFIGEYEPNLESLYSRQVTIDGEQVSLEIQDTPGQQQNEDpeSLERSLRWADGFVLVYSITDRSSF 88

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 389628760  97 EEITTFQQQILRVKDKDY-FPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSA-KSRINVDKAFYDIVREIRR 172
Cdd:cd04146   89 DVVSQLLQLIREIKKRDGeIPVILVGNKADLLHSRQVSTEEGQKLALELGCLFFEVSAaENYLEVQNVFHELCREVRR 166

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 389628760  22 KSCLTIQLIQS-HFVDEYDPTIEDSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:cd04148   13 KSSLANIFTAGvYEDSAYEASGDDTYERTVSVDGEEATLVVYDHWEQEDGMWLEDSCMQVGDAYVIVYSVTDRSSFEKAS 92

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 389628760 101 TFQQQILRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIR 171
Cdd:cd04148   93 ELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGIVRQVR 163

Rab GTPase families 8, 10, 13 (Rab8, Rab10, Rab13); Rab8/Sec4/Ypt2 are known or suspected to be involved in post-Golgi transport to the plasma membrane. It is likely that these Rabs have functions that are specific to the mammalian lineage and have no orthologs in plants. Rab8 modulates polarized membrane transport through reorganization of actin and microtubules, induces the formation of new surface extensions, and has an important role in directed membrane transport to cell surfaces. The Ypt2 gene of the fission yeast Schizosaccharomyces pombe encodes a member of the Ypt/Rab family of small GTP-binding proteins, related in sequence to Sec4p of Saccharomyces cerevisiae but closer to mammalian Rab8. 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 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCV-IDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:cd01867   16 KSCLLLRFSEDSFNPSFISTIGIDFKIRTIeLDGKKIKLQIWDTAGQERFRTITTSYYRGAMGIILVYDITDEKSFENIK 95

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 389628760 101 TFQQQILRVKDKDYFPMVVvGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIRR 172
Cdd:cd01867   96 NWMRNIDEHASEDVERMLV-GNKCDMEEKRVVSKEEGEALAREYGIKFLETSAKANINVEEAFLTLAKDILK 166

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 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSY-RKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:cd01860   14 KSSIVLRFVKNEFSENQESTIGAAFlTQTVNLDDTTVKFEIWDTAGQERYRSLAPMYYRGAAAAIVVYDITSEESFEKAK 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 101 TFQQQILRVKDKDYFpMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREI 170
Cdd:cd01860   94 SWVKELQEHGPPNIV-IALAGNKADLESKRQVSTEEAQEYADENGLLFMETSAKTGENVNELFTEIARKL 162

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCV-IDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:cd01866   17 KSCLLLQFTDKRFQPVHDLTIGVEFGARMItIDGKQIKLQIWDTAGQESFRSITRSYYRGAAGALLVYDITRRETFNHLT 96

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 101 TFQQQIlRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREI 170
Cdd:cd01866   97 SWLEDA-RQHSNSNMTIMLIGNKCDLESRREVSYEEGEAFAREHGLIFMETSAKTASNVEEAFINTAKEI 165

Rab GTPase family 11 (Rab11)-like includes Rab11a, Rab11b, and Rab25; Rab11a, Rab11b, and Rab25 are closely related, evolutionary conserved Rab proteins that are differentially expressed. Rab11a is ubiquitously synthesized, Rab11b is enriched in brain and heart and Rab25 is only found in epithelia. Rab11/25 proteins seem to regulate recycling pathways from endosomes to the plasma membrane and to the trans-Golgi network. Furthermore, Rab11a is thought to function in the histamine-induced fusion of tubulovesicles containing H+, K+ ATPase with the plasma membrane in gastric parietal cells and in insulin-stimulated insertion of GLUT4 in the plasma membrane of cardiomyocytes. Overexpression of Rab25 has recently been observed in ovarian cancer and breast cancer, and has been correlated with worsened outcomes in both diseases. In addition, Rab25 overexpression has also been observed in prostate cancer, transitional cell carcinoma of the bladder, and invasive breast tumor cells. 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 389628760  22 KSCLTIQLIQSHFVDEYDPTI--EDSYRkQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEI 99
Cdd:cd01868   16 KSNLLSRFTRNEFNLDSKSTIgvEFATR-TIQIDGKTIKAQIWDTAGQERYRAITSAYYRGAVGALLVYDITKKSTFENV 94

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 389628760 100 TTFQQQILRVKDKDYfPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREI 170
Cdd:cd01868   95 ERWLKELRDHADSNI-VIMLVGNKSDLRHLRAVPTEEAKAFAEKNGLSFIETSALDGTNVEEAFKQLLTEI 164

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  22 KSCLTIQLIQSHfVDEYDPTIEDSYR-KQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:PLN03118  27 KSSLLVSFISSS-VEDLAPTIGVDFKiKQLTVGGKRLKLTIWDTAGQERFRTLTSSYYRNAQGIILVYDVTRRETFTNLS 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 101 -TFQQQI-LRVKDKDYFPMVVvGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIrrynreMQ 178
Cdd:PLN03118 106 dVWGKEVeLYSTNQDCVKMLV-GNKVDRESERDVSREEGMALAKEHGCLFLECSAKTRENVEQCFEELALKI------ME 178

                        170       180       190
                 ....*....|....*....|....*....|...
gi 389628760 179 GYSTGSGGSNAGGPS--NKMEVNDSDAEAGCCS 209
Cdd:PLN03118 179 VPSLLEEGSTAVKRNilKQKPEHQPPPNGGCCS 211

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 389628760  22 KSCLTIQLIQSHFVDEYDPTIE-DSYRKQCVIDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIt 100
Cdd:cd01861   13 KTSIITRFMYDTFDNQYQATIGiDFLSKTMYVDDKTVRLQLWDTAGQERFRSLIPSYIRDSSVAVVVYDITNRQSFDNT- 91

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 389628760 101 tfQQQILRVKDK--DYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREI 170
Cdd:cd01861   92 --DKWIDDVRDErgNDVIIVLVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSAKAGHNVKQLFKKIAQAL 161

Rab GTPase family 39 (Rab39); Found in eukaryotes, Rab39 is mainly found in epithelial cell lines, but is distributed widely in various human tissues and cell lines. It is believed to be a novel Rab protein involved in regulating Golgi-associated vesicular transport during cellular endocytosis. 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 389628760  22 KSCLTIQLIQSHFVDEYDPTIE-DSYRKQCVIDDEVAL-LDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEI 99
Cdd:cd04111   15 KSSLLKRFTEGRFAEVSDPTVGvDFFSRLIEIEPGVRIkLQLWDTAGQERFRSITRSYYRNSVGVLLVFDITNRESFEHV 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 100 TTFQQQIlRVKDKDYFPM-VVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIrrYNR-EM 177
Cdd:cd04111   95 HDWLEEA-RSHIQPHRPVfILVGHKCDLESQRQVTREEAEKLAKDLGMKYIETSARTGDNVEEAFELLTQEI--YERiKR 171

                        170       180       190
                 ....*....|....*....|....*....|....*....
gi 389628760 178 QGYSTGSG------GSNAGG--PSNKMEVNDSDAEAGCC 208
Cdd:cd04111  172 GELCALDGwdgvksGFPAGRafSLEERSPTFASPEKSCC 210

Rab family protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760  22 KSCLTIQLIQSHFVDEYDPTIEDSYRKQCV-IDDEVALLDVLDTAGQEEYSAMREQYMRTGEGFLLVYSITSRQSFEEIT 100
Cdd:PLN03108  19 KSCLLLQFTDKRFQPVHDLTIGVEFGARMItIDNKPIKLQIWDTAGQESFRSITRSYYRGAAGALLVYDITRRETFNHLA 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389628760 101 TFQQQIlRVKDKDYFPMVVVGNKCDLEGEREVTRQEGEALARSFNCKFIETSAKSRINVDKAFYDIVREIRRYNRE---- 176
Cdd:PLN03108  99 SWLEDA-RQHANANMTIMLIGNKCDLAHRRAVSTEEGEQFAKEHGLIFMEASAKTAQNVEEAFIKTAAKIYKKIQDgvfd 177

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 389628760 177 --------MQGYSTGSGGSNAGGPSnkmevndSDAEAGCC 208
Cdd:PLN03108 178 vsnesygiKVGYGAIPGASGGRDGT-------SSQGGGCC 210