P-loop containing Nucleoside Triphosphate Hydrolases; Members of the P-loop NTPase domain superfamily are characterized by a conserved nucleotide phosphate-binding motif, also referred to as the Walker A motif (GxxxxGK[S/T], where x is any residue), and the Walker B motif (hhhh[D/E], where h is a hydrophobic residue). The Walker A and B motifs bind the beta-gamma phosphate moiety of the bound nucleotide (typically ATP or GTP) and the Mg2+ cation, respectively. The P-loop NTPases are involved in diverse cellular functions, and they can be divided into two major structural classes: the KG (kinase-GTPase) class which includes Ras-like GTPases and its circularly permutated YlqF-like; and the ASCE (additional strand catalytic E) class which includes ATPase Binding Cassette (ABC), DExD/H-like helicases, 4Fe-4S iron sulfur cluster binding proteins of NifH family, RecA-like F1-ATPases, and ATPases Associated with a wide variety of Activities (AAA). Also included are a diverse set of nucleotide/nucleoside kinase families.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115  86 RGAGHAEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALA 165
Cdd:cd04142   61 RYPGTAGQEWMDPRFRGLRNSRAFILVYDICSPDSFHYVKLLRQQILETRPAGNKEPPIVVVGNKRDQQRHRFAPRHVLS 140

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 768023115 166 ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVRARPAHPALRLQGALHPARCSLM 223
Cdd:cd04142  141 VLVRKSWKCGYLECSAKYNWHILLLFKELLISATTRGRSTHPALRLQGALHRERCSIM 198

Ras-related protein on chromosome 22 (RRP22) family; RRP22 (Ras-related protein on chromosome 22) subfamily consists of proteins that inhibit cell growth and promote caspase-independent cell death. Unlike most Ras proteins, RRP22 is down-regulated in many human tumor cells due to promoter methylation. RRP22 localizes to the nucleolus in a GTP-dependent manner, suggesting a novel function in modulating transport of nucleolar components. 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. Like most Ras family proteins, RRP22 is farnesylated.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115  86 RGAGHAEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALA 165
Cdd:cd04142   61 RYPGTAGQEWMDPRFRGLRNSRAFILVYDICSPDSFHYVKLLRQQILETRPAGNKEPPIVVVGNKRDQQRHRFAPRHVLS 140

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 768023115 166 ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVRARPAHPALRLQGALHPARCSLM 223
Cdd:cd04142  141 VLVRKSWKCGYLECSAKYNWHILLLFKELLISATTRGRSTHPALRLQGALHRERCSIM 198

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 768023115  105 DTDAFVLVYDICSPDSFDYVKALRQRIAETRPagaPEAPILVVGNK---RDRQRLRFGPRRALAalvrRGWRCGYLECSA 181
Cdd:pfam00071  71 GADGFLLVYDITSRDSFENVKKWVEEILRHAD---ENVPIVLVGNKcdlEDQRVVSTEEGEALA----KELGLPFMETSA 143

                          90
                  ....*....|....*
gi 768023115  182 KYNWHVLRLFRELLR 196
Cdd:pfam00071 144 KTNENVEEAFEELAR 158

GTPase SAR1 family domain [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115 102 SLQDTDAFVLVYDICSPDSFDYVKALRQRIAETrpagAPEAPILVVGNKRD-RQRLRFGPRRALAALVRRGWRCGYLECS 180
Cdd:COG1100   76 QLTGASLYLFVVDGTREETLQSLYELLESLRRL----GKKSPIILVLNKIDlYDEEEIEDEERLKEALSEDNIVEVVATS 151

                         90
                 ....*....|....*.
gi 768023115 181 AKYNWHVLRLFRELLR 196
Cdd:COG1100  152 AKTGEGVEELFAALAE 167

Ras-related protein on chromosome 22 (RRP22) family; RRP22 (Ras-related protein on chromosome 22) subfamily consists of proteins that inhibit cell growth and promote caspase-independent cell death. Unlike most Ras proteins, RRP22 is down-regulated in many human tumor cells due to promoter methylation. RRP22 localizes to the nucleolus in a GTP-dependent manner, suggesting a novel function in modulating transport of nucleolar components. 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. Like most Ras family proteins, RRP22 is farnesylated.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115  86 RGAGHAEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALA 165
Cdd:cd04142   61 RYPGTAGQEWMDPRFRGLRNSRAFILVYDICSPDSFHYVKLLRQQILETRPAGNKEPPIVVVGNKRDQQRHRFAPRHVLS 140

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 768023115 166 ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVRARPAHPALRLQGALHPARCSLM 223
Cdd:cd04142  141 VLVRKSWKCGYLECSAKYNWHILLLFKELLISATTRGRSTHPALRLQGALHRERCSIM 198

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 768023115  94 EWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRGWR 173
Cdd:cd04147   59 SFPAMRKLSIQNGDAFALVYSVDDPESFEEVKRLREEILEVK--EDKFVPIVVVGNKIDSLAERQVEAADALSTVELDWN 136

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 768023115 174 CGYLECSAKYNWHVLRLFRELLRCALVRARPAhPALR 210
Cdd:cd04147  137 NGFVEASAKDNENVTEVFKELLQQANLPSWLS-PALR 172

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 768023115  79 ASILERVRGAGhaEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRPAGAPEAPILVVGNKRDRQRLRF 158
Cdd:cd04144   46 PCMLEVLDTAG--QEEYTALRDQWIREGEGFILVYSITSRSTFERVERFREQIQRVKDESAADVPIMIVGNKCDKVYERE 123

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 768023115 159 GPRRALAALVRRgWRCGYLECSAKYNWHVLRLFRELLR 196
Cdd:cd04144  124 VSTEEGAALARR-LGCEFIEASAKTNVNVERAFYTLVR 160

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 768023115    93 EEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgW 172
Cdd:smart00173  59 EEFSAMRDQYMRTGEGFLLVYSITDRQSFEEIKKFREQILRVK--DRDDVPIVLVGNKCDLESERVVSTEEGKELARQ-W 135

                           90       100
                   ....*....|....*....|....
gi 768023115   173 RCGYLECSAKYNWHVLRLFRELLR 196
Cdd:smart00173 136 GCPFLETSAKERVNVDEAFYDLVR 159

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 768023115 107 DAFVLVYDICSPDSFDYVKALRQRIAETRPAG------APEAPILVVGNKRDRQRLRFGPRRALAALVRRGWRCGYLECS 180
Cdd:cd04143   73 DVFILVFSLDNRESFEEVCRLREQILETKSCLknktkeNVKIPMVICGNKADRDFPREVQRDEVEQLVGGDENCAYFEVS 152

                         90
                 ....*....|....
gi 768023115 181 AKYNWHVLRLFREL 194
Cdd:cd04143  153 AKKNSNLDEMFRAL 166

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 768023115  80 SILERVRGAGhaEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRD---RQRL 156
Cdd:cd04176   49 SVLEILDTAG--TEQFASMRDLYIKNGQGFIVVYSLVNQQTFQDIKPMRDQI--VRVKGYEKVPIILVGNKVDlesEREV 124

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 768023115 157 RFGPRRALAALvrrgWRCGYLECSAKYNWHVLRLFRELLR 196
Cdd:cd04176  125 SSAEGRALAEE----WGCPFMETSAKSKTMVNELFAEIVR 160

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 768023115 105 DTDAFVLVYDICSPDSFDYVKALrqrIAETRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRGwRCGYLECSAKYN 184
Cdd:cd00154   72 GAHGAILVYDVTNRESFENLDKW---LNELKEYAPPNIPIILVGNKSDLEDERQVSTEEAQQFAKEN-GLLFFETSAKTG 147

                         90
                 ....*....|..
gi 768023115 185 WHVLRLFRELLR 196
Cdd:cd00154  148 ENVDEAFESLAR 159

Rho (Ras homology) subfamily of Ras-like small GTPases; Members of this subfamily of Ras-like small GTPases include Cdc42 and Rac, as well as Rho isoforms.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115   102 SLQDTDAFVLVYDICSPDSFDYVKAlrQRIAETRpAGAPEAPILVVGNKRDrQRLRFGPRRALA-------------ALV 168
Cdd:smart00174  66 SYPDTDVFLICFSVDSPASFENVKE--KWYPEVK-HFCPNVPIILVGTKLD-LRNDKSTLEELSkkkqepvtyeqgqALA 141

                           90       100       110
                   ....*....|....*....|....*....|.
gi 768023115   169 RRGWRCGYLECSAKYNWHVLRLFRELLRCAL 199
Cdd:smart00174 142 KRIGAVKYLECSALTQEGVREVFEEAIRAAL 172

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 768023115 100 DWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAETRpagapEAPILVVGNKRDRQrlrfgPRRALAALVRRGWRCG---- 175
Cdd:cd00882   70 RLLLRGADLILLVVDSTDRESEEDAKLLILRRLRKE-----GIPIILVGNKIDLL-----EEREVEELLRLEELAKilgv 139

                         90       100
                 ....*....|....*....|..
gi 768023115 176 -YLECSAKYNWHVLRLFRELLR 196
Cdd:cd00882  140 pVFEVSAKTGEGVDELFEKLIE 161

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115   107 DAFVLVYDICSPDSFDYVKALRQRIAETRPagaPEAPILVVGNKRDRQRLRFGPRRALAALVRRGwRCGYLECSAKYNWH 186
Cdd:smart00175  74 VGALLVYDITNRESFENLENWLKELREYAS---PNVVIMLVGNKSDLEEQRQVSREEAEAFAEEH-GLPFFETSAKTNTN 149

                           90
                   ....*....|
gi 768023115   187 VLRLFRELLR 196
Cdd:smart00175 150 VEEAFEELAR 159

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 768023115  80 SILERVRGAGhaEEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFG 159
Cdd:cd04136   49 CMLEILDTAG--TEQFTAMRDLYIKNGQGFALVYSITAQQSFNDLQDLREQI--LRVKDTEDVPMILVGNKCDLEDERVV 124

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 768023115 160 PRRALAALVRRGWRCGYLECSAKYNWHVLRLFRELLR 196
Cdd:cd04136  125 SKEEGQNLARQWGNCPFLETSAKSKINVDEIFYDLVR 161

Ras homology family A (RhoA)-like includes RhoA, RhoB and RhoC; The RhoA subfamily consists of RhoA, RhoB, and RhoC. RhoA promotes the formation of stress fibers and focal adhesions, regulating cell shape, attachment, and motility. RhoA can bind to multiple effector proteins, thereby triggering different downstream responses. In many cell types, RhoA mediates local assembly of the contractile ring, which is necessary for cytokinesis. RhoA is vital for muscle contraction; in vascular smooth muscle cells, RhoA plays a key role in cell contraction, differentiation, migration, and proliferation. RhoA activities appear to be elaborately regulated in a time- and space-dependent manner to control cytoskeletal changes. Most Rho 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 Rho proteins. RhoA and RhoC are observed only in geranylgeranylated forms; however, RhoB can be present in palmitoylated, farnesylated, and geranylgeranylated forms. RhoA and RhoC are highly relevant for tumor progression and invasiveness; however, RhoB has recently been suggested to be a tumor suppressor. 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 768023115 102 SLQDTDAFVLVYDICSPDSFDYVKalRQRIAETRPAgAPEAPILVVGNKRDrqrLRFGP--RRALA-------------A 166
Cdd:cd01870   69 SYPDTDVILMCFSIDSPDSLENIP--EKWTPEVKHF-CPNVPIILVGNKKD---LRNDEhtIRELAkmkqepvkpeegrA 142

                         90       100       110
                 ....*....|....*....|....*....|...
gi 768023115 167 LVRRGWRCGYLECSAKYNWHVLRLFRELLRCAL 199
Cdd:cd01870  143 MAEKIGAFGYLECSAKTKEGVREVFEMATRAAL 175

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 768023115  99 KDWSLQDTDAFVLVYDICSPDSFDYVKALRQRIAetRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLE 178
Cdd:cd04139   65 RDNYFRSGEGFLLVFSITDMESFTALAEFREQIL--RVKEDDNVPLLLVGNKCDLEDKRQVSVEEAANLAEQ-WGVNYVE 141

                         90
                 ....*....|....*...
gi 768023115 179 CSAKYNWHVLRLFRELLR 196
Cdd:cd04139  142 TSAKTRANVDKVFFDLVR 159

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 768023115 109 FVLVYDICSPDSFDYVKALRQRIaeTRPAGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRGWRCGYLECSAKYNWHVL 188
Cdd:cd04177   76 FLLVYSVTSEASLNELGELREQV--LRIKDSDNVPMVLVGNKADLEDDRQVSREDGVSLSQQWGNVPFYETSARKRTNVD 153

                 ....*...
gi 768023115 189 RLFRELLR 196
Cdd:cd04177  154 EVFIDLVR 161

Ras homology family 4 (Rho4) of small guanosine triphosphatases (GTPases)-like; Rho4 is a GTPase that controls septum degradation by regulating secretion of Eng1 or Agn1 during cytokinesis. Rho4 also plays a role in cell morphogenesis. Rho4 regulates septation and cell morphology by controlling the actin cytoskeleton and cytoplasmic microtubules. The localization of Rho4 is modulated by Rdi1, which may function as a GDI, and by Rga9, which is believed to function as a GAP. In S. pombe, both Rho4 deletion and Rho4 overexpression result in a defective cell wall, suggesting a role for Rho4 in maintaining cell wall integrity. Most Rho 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 Rho proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115 102 SLQDTDAFVLVYDICSPDSFDYVKALrqriaetrpaGAPE-------APILVVGNK----RDRQRLRFGPRRALA----- 165
Cdd:cd04132   72 SYPDVDVILICYSVDNPTSLDNVEDK----------WYPEvnhfcpgTPIVLVGLKtdlrKDKNSVSKLRAQGLEpvtpe 141

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 768023115 166 ---ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVRARPA 205
Cdd:cd04132  142 qgeSVAKSIGAVAYIECSAKLMENVDEVFDAAINVALSKSGRA 184

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 768023115 105 DTDAFVLVYDICSPDSFDYVkalRQRIAETRPAGAPEAPILVVGNKRDRQRLRFGPR---RALAALVrrgwRCGYLECSA 181
Cdd:cd04123   72 DADGAILVYDITDADSFQKV---KKWIKELKQMRGNNISLVIVGNKIDLERQRVVSKseaEEYAKSV----GAKHFETSA 144

                         90
                 ....*....|...
gi 768023115 182 KYNWHVLRLFREL 194
Cdd:cd04123  145 KTGKGIEELFLSL 157

Ras homology family 3 (Rho3) of small guanosine triphosphatases (GTPases); Rho3 is a member of the Rho family found only in fungi. Rho3 is believed to regulate cell polarity by interacting with the diaphanous/formin family protein For3 to control both the actin cytoskeleton and microtubules. Rho3 is also believed to have a direct role in exocytosis that is independent of its role in regulating actin polarity. The function in exocytosis may be two-pronged: first, in the transport of post-Golgi vesicles from the mother cell to the bud, mediated by myosin (Myo2); second, in the docking and fusion of vesicles to the plasma membrane, mediated by an exocyst (Exo70) protein. Most Rho 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 Rho proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115  92 EEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKAlrQRIAETRpAGAPEAPILVVGNK---RDRQRLRFGPRRALA--- 165
Cdd:cd04134   58 QEEFDRLRSLSYADTHVIMLCFSVDNPDSLENVES--KWLAEIR-HHCPGVKLVLVALKcdlREPRNERDRGTHTISyee 134

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 768023115 166 --ALVRRGWRCGYLECSAKYNWHVLRLFRELLRCALVrARPAHP 207
Cdd:cd04134  135 glAVAKRINACRYLECSAKLNRGVNEAFTEAARVALN-ARPPHP 177

Wnt-1 responsive Cdc42 homolog (Wrch-1) is a Rho family GTPase similar to Cdc42; Wrch-1 (Wnt-1 responsive Cdc42 homolog) is a Rho family GTPase that shares significant sequence and functional similarity with Cdc42. Wrch-1 was first identified in mouse mammary epithelial cells, where its transcription is upregulated in Wnt-1 transformation. Wrch-1 contains N- and C-terminal extensions relative to cdc42, suggesting potential differences in cellular localization and function. The Wrch-1 N-terminal extension contains putative SH3 domain-binding motifs and has been shown to bind the SH3 domain-containing protein Grb2, which increases the level of active Wrch-1 in cells. Unlike Cdc42, which localizes to the cytosol and perinuclear membranes, Wrch-1 localizes extensively with the plasma membrane and endosomes. The membrane association, localization, and biological activity of Wrch-1 indicate an atypical model of regulation distinct from other Rho family GTPases. Most Rho 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 Rho 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 768023115 105 DTDAFVLVYDICSPDSFDYVKalRQRIAETRpAGAPEAPILVVGNKRD----------RQRLRFGPRRALAA--LVRRGW 172
Cdd:cd04130   71 DTDVFLLCFSVVNPSSFQNIS--EKWIPEIR-KHNPKAPIILVGTQADlrtdvnvliqLARYGEKPVSQSRAkaLAEKIG 147

                 ....*....
gi 768023115 173 RCGYLECSA 181
Cdd:cd04130  148 ACEYIECSA 156

Rho family GTPase subfamily Rnd includes Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8; The Rnd subfamily contains Rnd1/Rho6, Rnd2/Rho7, and Rnd3/RhoE/Rho8. These novel Rho family proteins have substantial structural differences compared to other Rho members, including N- and C-terminal extensions relative to other Rhos. Rnd3/RhoE is farnesylated at the C-terminal prenylation site, unlike most other Rho proteins that are geranylgeranylated. In addition, Rnd members are unable to hydrolyze GTP and are resistant to GAP activity. They are believed to exist only in the GTP-bound conformation, and are antagonists of RhoA activity. Most Rho 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 Rho 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 768023115 102 SLQDTDAFVLVYDICSPDSFDYVkaLRQRIAETRPAGaPEAPILVVGNKRD-RQRL---------RFGPRRAL--AALVR 169
Cdd:cd04131   69 SYPDSDAVLICFDISRPETLDSV--LKKWKGEVREFC-PNTPVLLVGCKSDlRTDLstltelsnkRQIPVSHEqgRNLAK 145

                         90
                 ....*....|...
gi 768023115 170 RGWRCGYLECSAK 182
Cdd:cd04131  146 QIGAAAYVECSAK 158

Ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)-like consists of Rac1, Rac2 and Rac3; The Rac1-like subfamily consists of Rac1, Rac2, and Rac3 proteins, plus the splice variant Rac1b that contains a 19-residue insertion near switch II relative to Rac1. While Rac1 is ubiquitously expressed, Rac2 and Rac3 are largely restricted to hematopoietic and neural tissues respectively. Rac1 stimulates the formation of actin lamellipodia and membrane ruffles. It also plays a role in cell-matrix adhesion and cell anoikis. In intestinal epithelial cells, Rac1 is an important regulator of migration and mediates apoptosis. Rac1 is also essential for RhoA-regulated actin stress fiber and focal adhesion complex formation. In leukocytes, Rac1 and Rac2 have distinct roles in regulating cell morphology, migration, and invasion, but are not essential for macrophage migration or chemotaxis. Rac3 has biochemical properties that are closely related to Rac1, such as effector interaction, nucleotide binding, and hydrolysis; Rac2 has a slower nucleotide association and is more efficiently activated by the RacGEF Tiam1. Both Rac1 and Rac3 have been implicated in the regulation of cell migration and invasion in human metastatic breast cancer. Most Rho 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 Rho 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 768023115  92 EEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVKAlrQRIAETRpAGAPEAPILVVGNKRD-------RQRLRfgPRRAL 164
Cdd:cd01871   59 QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRA--KWYPEVR-HHCPNTPIILVGTKLDlrddkdtIEKLK--EKKLT 133

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 768023115 165 AALVRRGWRCG-------YLECSAKYNWHVLRLFRELLR 196
Cdd:cd01871  134 PITYPQGLAMAkeigavkYLECSALTQRGLKTVFDEAIR 172

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 768023115 110 VLVYDICSPDSFDYVKALRQRIAETrpaGAPEAPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLECSAKYNWHVLR 189
Cdd:cd01867   80 ILVYDITDEKSFENIKNWMRNIDEH---ASEDVERMLVGNKCDMEEKRVVSKEEGEALARE-YGIKFLETSAKANINVEE 155

                 ....*..
gi 768023115 190 LFRELLR 196
Cdd:cd01867  156 AFLTLAK 162

Ras homology family 2 (Rho2) of small guanosine triphosphatases (GTPases); Rho2 is a fungal GTPase that plays a role in cell morphogenesis, control of cell wall integrity, control of growth polarity, and maintenance of growth direction. Rho2 activates the protein kinase C homolog Pck2, and Pck2 controls Mok1, the major (1-3) alpha-D-glucan synthase. Together with Rho1 (RhoA), Rho2 regulates the construction of the cell wall. Unlike Rho1, Rho2 is not an essential protein, but its overexpression is lethal. Most Rho 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 proper intracellular localization via membrane attachment. As with other Rho family GTPases, the GDP/GTP cycling is regulated by GEFs (guanine nucleotide exchange factors), GAPs (GTPase-activating proteins) and GDIs (guanine nucleotide dissociation inhibitors).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768023115  92 EEEWPDAKDWSLQDTDAFVLVYDICSPDSFDYVkalRQRIAETRPAGAPEAPILVVGNKRD-RQRLRFGPRRALAALVRR 170
Cdd:cd04129   59 QEEYERLRPLSYSKAHVILIGFAIDTPDSLENV---RTKWIEEVRRYCPNVPVILVGLKKDlRQEAVAKGNYATDEFVPI 135

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 768023115 171 ----------GWRcGYLECSAKYNWHVLRLFRELLRCALV 200
Cdd:cd04129  136 qqaklvaraiGAK-KYMECSALTGEGVDDVFEAATRAALL 174

Rab GTPase family 40 (Rab40) contains Rab40a, Rab40b and Rab40c; The Rab40 subfamily contains Rab40a, Rab40b, and Rab40c, which are all highly homologous. In rat, Rab40c is localized to the perinuclear recycling compartment (PRC), and is distributed in a tissue-specific manor, with high expression in brain, heart, kidney, and testis, low expression in lung and liver, and no expression in spleen and skeletal muscle. Rab40c is highly expressed in differentiated oligodendrocytes but minimally expressed in oligodendrocyte progenitors, suggesting a role in the vesicular transport of myelin components. Unlike most other Ras-superfamily proteins, Rab40c was shown to have a much lower affinity for GTP, and an affinity for GDP that is lower than for 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. 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 768023115 110 VLVYDICSPDSFDYVKALRQRIAETrpagAPEAPILVVGNkrdrqRLRFGPRRALAALVRRGW--RCG--YLECSAKYNW 185
Cdd:cd04121   83 ILVYDITNRWSFDGIDRWIKEIDEH----APGVPKILVGN-----RLHLAFKRQVATEQAQAYaeRNGmtFFEVSPLCNF 153

                         90
                 ....*....|....*.
gi 768023115 186 HVLRLFRELLRCALVR 201
Cdd:cd04121  154 NITESFTELARIVLMR 169

Rab GTPase family 27a (Rab27a); The Rab27a subfamily consists of Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4. Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy. When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers. 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 768023115 103 LQDTDAFVLVYDICSPDSF----DYVKALRQRIAETRPagapeaPILVVGNKRDRQRLRFGPRRALAALVRRgWRCGYLE 178
Cdd:cd04127   84 FRDAMGFLLMFDLTSEQSFlnvrNWMSQLQAHAYCENP------DIVLIGNKADLPDQREVSERQARELADK-YGIPYFE 156

                 ...
gi 768023115 179 CSA 181
Cdd:cd04127  157 TSA 159