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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04139   1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQLNILDTAGQEDYAAIRDNYFRSGEGFLLVFS 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKsEEDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04139  81 ITDMESFTALAEFREQILRVK-EDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFFDLVR 159

                ....
gi 11612509 175 EIRA 178
Cdd:cd04139 160 EIRQ 163

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04139   1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQLNILDTAGQEDYAAIRDNYFRSGEGFLLVFS 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKsEEDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04139  81 ITDMESFTALAEFREQILRVK-EDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFFDLVR 159

                ....
gi 11612509 175 EIRA 178
Cdd:cd04139 160 EIRQ 163

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509    16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPT-KADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTiGVDFYTKTIEVDGKTVKLQIWDTAGQERFRALRPLYYRGADGFLLVYD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509    95 ITEHESFTATAEFREQILRVKSeeDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:pfam00071  81 ITSRDSFENVKKWVEEILRHAD--ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVEEAFEELAR 158

                  ...
gi 11612509   175 EIR 177
Cdd:pfam00071 159 EIL 161

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  16 KVIMVGSGGVGKSALTLQFMYDEF-VEDYEPT-KADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEG---FL 90
Cdd:COG1100   5 KIVVVGTGGVGKTSLVNRLVGDIFsLEKYLSTnGVTIDKKELKLDGLDVDLVIWDTPGQDEFRETRQFYARQLTGaslYL 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  91 LVFSITEHESFTATAEFREQILRVKseeDKIPLLVVGNKSDL-EERRQVPVDEARGKAEEWGVQ-YVETSAKTRANVDKV 168
Cdd:COG1100  85 FVVDGTREETLQSLYELLESLRRLG---KKSPIILVLNKIDLyDEEEIEDEERLKEALSEDNIVeVVATSAKTGEGVEEL 161

                       170
                ....*....|
gi 11612509 169 FFDLMREIRA 178
Cdd:COG1100 162 FAALAEILRG 171

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04139   1 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQLNILDTAGQEDYAAIRDNYFRSGEGFLLVFS 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKsEEDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04139  81 ITDMESFTALAEFREQILRVK-EDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQWGVNYVETSAKTRANVDKVFFDLVR 159

                ....
gi 11612509 175 EIRA 178
Cdd:cd04139 160 EIRQ 163

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 11612509     15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:smart00173   1 YKLVVLGSGGVGKSALTIQFIQGHFVDDYDPTIEDSYRKQIEIDGEVCLLDILDTAGQEEFSAMRDQYMRTGEGFLLVYS 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509     95 ITEHESFTATAEFREQILRVKSEEDkIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:smart00173  81 ITDRQSFEEIKKFREQILRVKDRDD-VPIVLVGNKCDLESERVVSTEEGKELARQWGCPFLETSAKERVNVDEAFYDLVR 159

                   ....*
gi 11612509    175 EIRAK 179
Cdd:smart00173 160 EIRKK 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 11612509    16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPT-KADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTiGVDFYTKTIEVDGKTVKLQIWDTAGQERFRALRPLYYRGADGFLLVYD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509    95 ITEHESFTATAEFREQILRVKSeeDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:pfam00071  81 ITSRDSFENVKKWVEEILRHAD--ENVPIVLVGNKCDLEDQRVVSTEEGEALAKELGLPFMETSAKTNENVEEAFEELAR 158

                  ...
gi 11612509   175 EIR 177
Cdd:pfam00071 159 EIL 161

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04145   3 YKLVVVGGGGVGKSALTIQFIQSYFVTDYDPTIEDSYTKQCEIDGQWARLDILDTAGQEEFSAMREQYMRTGEGFLLVFS 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEEDkIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04145  83 VTDRGSFEEVDKFHTQILRVKDRDE-FPMILVGNKADLEHQRQVSREEGQELARQLKIPYIETSAKDRVNVDKAFHDLVR 161

                ...
gi 11612509 175 EIR 177
Cdd:cd04145 162 VIR 164

Ras-like protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509   15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:PTZ00369   6 YKLVVVGGGGVGKSALTIQFIQNHFIDEYDPTIEDSYRKQCVIDEETCLLDILDTAGQEEYSAMRDQYMRTGQGFLCVYS 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509   95 ITEHESFTATAEFREQILRVKsEEDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:PTZ00369  86 ITSRSSFEEIASFREQILRVK-DKDRVPMILVGNKCDLDSERQVSTGEGQELAKSFGIPFLETSAKQRVNVDEAFYELVR 164

                        170
                 ....*....|....*....
gi 11612509  175 EIRA---KKMSENKDKNGR 190
Cdd:PTZ00369 165 EIRKylkEDMPSQKQKKKG 183

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04175   2 YKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDGQQCMLEILDTAGTEQFTAMRDLYMKNGQGFVLVYS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEEDkIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04175  82 ITAQSTFNDLQDLREQILRVKDTED-VPMILVGNKCDLEDERVVGKEQGQNLARQWGCAFLETSAKAKINVNEIFYDLVR 160

                ..
gi 11612509 175 EI 176
Cdd:cd04175 161 QI 162

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04176   2 YKVVVLGSGGVGKSALTVQFVSGTFIEKYDPTIEDFYRKEIEVDSSPSVLEILDTAGTEQFASMRDLYIKNGQGFIVVYS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEEdKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04176  82 LVNQQTFQDIKPMRDQIVRVKGYE-KVPIILVGNKVDLESEREVSSAEGRALAEEWGCPFMETSAKSKTMVNELFAEIVR 160

                ..
gi 11612509 175 EI 176
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 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYR-KKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd00154   2 KIVLIGDSGVGKTSLLLRFVDNKFSENYKSTIGVDFKsKTIEVDGKKVKLQIWDTAGQERFRSITSSYYRGAHGAILVYD 81

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 11612509  95 ITEHESFTATAEFREQILRVKSEedKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDL 172
Cdd:cd00154  82 VTNRESFENLDKWLNELKEYAPP--NIPIILVGNKSDLEDERQVSTEEAQQFAKENGLLFFETSAKTGENVDEAFESL 157

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFSI 95
Cdd:cd04137   3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPTIENTFSKIITYKGQEYHLEIVDTAGQDEYSILPQKYSIGIHGYILVYSV 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  96 TEHESFTATAEFREQILRVKSEEdKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMRE 175
Cdd:cd04137  83 TSRKSFEVVKVIYDKILDMLGKE-SVPIVLVGNKSDLHMERQVSAEEGKKLAESWGAAFLESSAKENENVEEAFELLIEE 161

                .
gi 11612509 176 I 176
Cdd:cd04137 162 I 162

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04143   1 YRMVVLGASKVGKTAIVSRFLGGRFEEQYTPTIEDFHRKLYSIRGEVYQLDILDTSGNHPFPAMRRLSILTGDVFILVFS 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKS-------EEDKIPLLVVGNKSDLEERRQVPVDEARG-KAEEWGVQYVETSAKTRANVD 166
Cdd:cd04143  81 LDNRESFEEVCRLREQILETKSclknktkENVKIPMVICGNKADRDFPREVQRDEVEQlVGGDENCAYFEVSAKKNSNLD 160

                ....*.
gi 11612509 167 KVFFDL 172
Cdd:cd04143 161 EMFRAL 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 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVE-DYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04148   2 RVVLLGDSGVGKSSLANIFTAGVYEDsAYEASGDDTYERTVSVDGEEATLVVYDHWEQEDGMWLEDSCMQVGDAYVIVYS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEEDkIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04148  82 VTDRSSFEKASELRIQLRRARQAED-IPIILVGNKSDLVRSREVSVQEGRACAVVFDCKFIETSAALQHNVDELFEGIVR 160

                       170
                ....*....|....*.
gi 11612509 175 EIRAKKMSENKDKNGR 190
Cdd:cd04148 161 QVRLRRDSKEKNTRRM 176

Rab GTPase family 21 (Rab21); The localization and function of Rab21 are not clearly defined, with conflicting data reported. Rab21 has been reported to localize in the ER in human intestinal epithelial cells, with partial colocalization with alpha-glucosidase, a late endosomal/lysosomal marker. More recently, Rab21 was shown to colocalize with and affect the morphology of early endosomes. In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis. 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 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADS-YRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04123   2 KVVLLGEGRVGKTSLVLRYVENKFNEKHESTTQASfFQKTVNIGGKRIDLAIWDTAGQERYHALGPIYYRDADGAILVYD 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQIlrVKSEEDKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLMR 174
Cdd:cd04123  82 ITDADSFQKVKKWIKEL--KQMRGNNISLVIVGNKIDLERQRVVSKSEAEEYAKSVGAKHFETSAKTGKGIEELFLSLAK 159

                ..
gi 11612509 175 EI 176
Cdd:cd04123 160 RM 161

Ras - dorsal-ventral anterior localization (Ras-dva) family; Ras-dva subfamily. Ras-dva (Ras - dorsal-ventral anterior localization) subfamily consists of a set of proteins characterized only in Xenopus leavis, to date. In Xenopus Ras-dva expression is activated by the transcription factor Otx2 and begins during gastrulation throughout the anterior ectoderm. Ras-dva expression is inhibited in the anterior neural plate by factor Xanf1. Downregulation of Ras-dva results in head development abnormalities through the inhibition of several regulators of the anterior neural plate and folds patterning, including Otx2, BF-1, Xag2, Pax6, Slug, and Sox9. Downregulation of Ras-dva also interferes with the FGF-8a signaling within the anterior ectoderm. 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 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFSI 95
Cdd:cd04147   1 RLVFMGAAGVGKTALIQRFLYDTFEPKHRRTVEELHSKEYEVAGVKVTIDILDTSGSYSFPAMRKLSIQNGDAFALVYSV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  96 TEHESFTATAEFREQILRVKseEDK-IPLLVVGNKSDLEERRQVPVDEARGKAE-EWGVQYVETSAKTRANVDKVFFDLM 173
Cdd:cd04147  81 DDPESFEEVKRLREEILEVK--EDKfVPIVVVGNKIDSLAERQVEAADALSTVElDWNNGFVEASAKDNENVTEVFKELL 158

                ....
gi 11612509 174 REIR 177
Cdd:cd04147 159 QQAN 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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKA-DSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVF 93
Cdd:cd01861   1 HKLVFLGDQSVGKTSIITRFMYDTFDNQYQATIGiDFLSKTMYVDDKTVRLQLWDTAGQERFRSLIPSYIRDSSVAVVVY 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 11612509  94 SITEHESFTATaefREQILRVKSEEDKIPLLV-VGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVF 169
Cdd:cd01861  81 DITNRQSFDNT---DKWIDDVRDERGNDVIIVlVGNKTDLSDKRQVSTEEGEKKAKENNAMFIETSAKAGHNVKQLF 154

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 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd04140   2 YRVVVFGAGGVGKSSLVLRFVKGTFRESYIPTIEDTYRQVISCSKSICTLQITDTTGSHQFPAMQRLSISKGHAFILVYS 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEE-DKIPLLVVGNKSDLEERRQVPVDEARGKAEEWGVQYVETSAKTRANVDKVFFDLM 173
Cdd:cd04140  82 ITSKQSLEELKPIYELICEIKGNNlEKIPIMLVGNKCDESPSREVSSSEGAALARTWNCAFMETSAKTNHNVQELFQELL 161

Rab GTPase family 7 (Rab7); Rab7 subfamily. Rab7 is a small Rab GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. The yeast Ypt7 and mammalian Rab7 are both involved in transport to the vacuole/lysosome, whereas Ypt7 is also required for homotypic vacuole fusion. Mammalian Rab7 is an essential participant in the autophagic pathway for sequestration and targeting of cytoplasmic components to the lytic compartment. Mammalian Rab7 is also proposed to function as a tumor suppressor. 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 11612509  16 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPT-KADSYRKKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVFS 94
Cdd:cd01862   2 KVIILGDSGVGKTSLMNQYVNKKFSNQYKATiGADFLTKEVTVDDRLVTLQIWDTAGQERFQSLGVAFYRGADCCVLVYD 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  95 ITEHESFTATAEFREQILRVKSEED--KIPLLVVGNKSDLEERRQVPVDeargKAEEWGV-----QYVETSAKTRANVDK 167
Cdd:cd01862  82 VTNPKSFESLDSWRDEFLIQASPRDpeNFPFVVLGNKIDLEEKRQVSTK----KAQQWCKskgniPYFETSAKEAINVDQ 157

                ....*..
gi 11612509 168 VFFDLMR 174
Cdd:cd01862 158 AFETIAR 164

Rab GTPase family J-like (RabJ-like); RJLs are found in many protists and as chimeras with C-terminal DNAJ domains in deuterostome metazoa. They are not found in plants, fungi, and protostome metazoa, suggesting a horizontal gene transfer between protists and deuterostome metazoa. RJLs lack any known membrane targeting signal and contain a degenerate phosphate/magnesium-binding 3 (PM3) motif, suggesting an impaired ability to hydrolyze GTP. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11612509  15 HKVIMVGSGGVGKSALTLQFMYDEFVEDYEPTKADSYR-KKVVLDGEEVQIDILDTAGQEDYAAIRDNYFRSGEGFLLVF 93
Cdd:cd04119   1 IKVISMGNSGVGKSCIIKRYCEGRFVSKYLPTIGIDYGvKKVSVRNKEVRVNFFDLSGHPEYLEVRNEFYKDTQGVLLVY 80