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 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAGPGsSPGGPEEWPDAKDWSLQ 84
Cdd:cd04142   1 VRVAVLGAPGVGKTAIVRQFLAQEFPEEYIPTEHRRLYRPAVVLSGRVYDLHILDVPNMQRY-PGTAGQEWMDPRFRGLR 79

                        90       100       110
                ....*....|....*....|....*....|.
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04142  80 NSRAFILVYDICSPDSFHYVKLLRQQILETR 110

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 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAGPGsSPGGPEEWPDAKDWSLQ 84
Cdd:cd04142   1 VRVAVLGAPGVGKTAIVRQFLAQEFPEEYIPTEHRRLYRPAVVLSGRVYDLHILDVPNMQRY-PGTAGQEWMDPRFRGLR 79

                        90       100       110
                ....*....|....*....|....*....|.
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04142  80 NSRAFILVYDICSPDSFHYVKLLRQQILETR 110

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 45708770     6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRLYRPAVLLDGAVYDLSIRdgDVAgpgsspgGPEEWPDAKDWSLQD 85
Cdd:pfam00071   1 KLVLVGDGGVGKSSLLIRFTQNKFPEEYIPTIGVDFYTKTIEVDGKTVKLQIW--DTA-------GQERFRALRPLYYRG 71

                          90       100
                  ....*....|....*....|....*.
gi 45708770    86 TDAFVLVYDICSPDSFDYVKALRQRI 111
Cdd:pfam00071  72 ADGFLLVYDITSRDSFENVKKWVEEI 97

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 45708770   3 GSLRVAVLGAPGVGKTAIIRQFLfGDY--PERHRPTDGPRLYRPAVLLDGAVYDLSIRD 59
Cdd:COG1100   2 GEKKIVVVGTGGVGKTSLVNRLV-GDIfsLEKYLSTNGVTIDKKELKLDGLDVDLVIWD 59

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 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAGPGsSPGGPEEWPDAKDWSLQ 84
Cdd:cd04142   1 VRVAVLGAPGVGKTAIVRQFLAQEFPEEYIPTEHRRLYRPAVVLSGRVYDLHILDVPNMQRY-PGTAGQEWMDPRFRGLR 79

                        90       100       110
                ....*....|....*....|....*....|.
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04142  80 NSRAFILVYDICSPDSFHYVKLLRQQILETR 110

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDgPRLYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQD 85
Cdd:cd04147   1 RLVFMGAAGVGKTALIQRFLYDTFEPKHRRTV-EELHSKEYEVAGVKVTIDILD---------TSGSYSFPAMRKLSIQN 70

                        90       100       110
                ....*....|....*....|....*....|
gi 45708770  86 TDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04147  71 GDAFALVYSVDDPESFEEVKRLREEILEVK 100

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770      6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSL 83
Cdd:smart00010   4 KLVVLGGGGVGKSALTIQFVQGHFVDEYDPTieDS---YRKQIEIDGEVCLLDILD---------TAGQEEFSAMRDQYM 71

                           90       100       110
                   ....*....|....*....|....*....|..
gi 45708770     84 QDTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:smart00010  72 RTGEGFLLVYSITDRQSFEEIAKFREQILRVK 103

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 45708770   7 VAVLGAPGVGKTAIIRQFL----FGDYperhRPTDGpRLYRPAVLLDGAVYDLSIRDgdvagpgsSPGGP-EEWPDAKDW 81
Cdd:cd04146   2 IAVLGASGVGKSALTVRFLtkrfIGEY----EPNLE-SLYSRQVTIDGEQVSLEIQD--------TPGQQqNEDPESLER 68

                        90       100       110
                ....*....|....*....|....*....|....
gi 45708770  82 SLQDTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04146  69 SLRWADGFVLVYSITDRSSFDVVSQLLQLIREIK 102

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSL 83
Cdd:cd04177   3 KIVVLGAGGVGKSALTVQFVQNVFIESYDPTieDS---YRKQVEIDGRQCDLEILD---------TAGTEQFTAMRELYI 70

                        90       100
                ....*....|....*....|....*...
gi 45708770  84 QDTDAFVLVYDICSPDSFDYVKALRQRI 111
Cdd:cd04177  71 KSGQGFLLVYSVTSEASLNELGELREQV 98

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDgPRLYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQD 85
Cdd:cd04136   3 KLVVLGSGGVGKSALTVQFVQGIFVDKYDPTI-EDSYRKQIEVDCQQCMLEILD---------TAGTEQFTAMRDLYIKN 72

                        90       100
                ....*....|....*....|....*.
gi 45708770  86 TDAFVLVYDICSPDSFDYVKALRQRI 111
Cdd:cd04136  73 GQGFALVYSITAQQSFNDLQDLREQI 98

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSL 83
Cdd:cd04175   3 KLVVLGSGGVGKSALTVQFVQGIFVEKYDPTieDS---YRKQVEVDGQQCMLEILD---------TAGTEQFTAMRDLYM 70

                        90       100       110
                ....*....|....*....|....*....|..
gi 45708770  84 QDTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04175  71 KNGQGFVLVYSITAQSTFNDLQDLREQILRVK 102

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 45708770   8 AVLGAPGVGKTAIIRQFL---FGDYPERHRPTDGPRLYRpaVLLDGAVYDLSIRDGdvagPGSSPGGPEEWPDAKDWSLQ 84
Cdd:cd00882   1 VVVGRGGVGKSSLLNALLggeVGEVSDVPGTTRDPDVYV--KELDKGKVKLVLVDT----PGLDEFGGLGREELARLLLR 74

                        90       100
                ....*....|....*....|....
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALR 108
Cdd:cd00882  75 GADLILLVVDSTDRESEEDAKLLI 98

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDgPRLYRPAVLLDGAVYDLSIRDGDvagpgsspgGPEEWPDAKDWSLQD 85
Cdd:cd04140   3 RVVVFGAGGVGKSSLVLRFVKGTFRESYIPTI-EDTYRQVISCSKSICTLQITDTT---------GSHQFPAMQRLSISK 72

                        90       100       110
                ....*....|....*....|....*....|
gi 45708770  86 TDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04140  73 GHAFILVYSITSKQSLEELKPIYELICEIK 102

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSL 83
Cdd:cd04139   2 KVIMVGSGGVGKSALTLQFMYDEFVEDYEPTkaDS---YRKKVVLDGEEVQLNILD---------TAGQEDYAAIRDNYF 69

                        90       100
                ....*....|....*....|....*...
gi 45708770  84 QDTDAFVLVYDICSPDSFDYVKALRQRI 111
Cdd:cd04139  70 RSGEGFLLVFSITDMESFTALAEFREQI 97

Mitochondrial Rho family 2 (Miro2), C-terminal; Miro2 subfamily. Miro (mitochondrial Rho) proteins have tandem GTP-binding domains separated by a linker region containing putative calcium-binding EF hand motifs. Genes encoding Miro-like proteins were found in several eukaryotic organisms. This CD represents the putative GTPase domain in the C terminus of Miro proteins. These atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. Most Rho proteins contain a lipid modification site at the C-terminus; however, Miro is one of few Rho subfamilies that lack this feature.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770   9 VLGAPGVGKTAIIRQFLFGDY-PERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAGPGsspggpeewPDAKDWSLQDTD 87
Cdd:cd01892   9 VLGAKGSGKSALLQAFLGRSFsQNAYSPTIKPRYAVNTVEVPGQEKYLILREVGEDEEA---------ILLNDAELAACD 79

                        90       100
                ....*....|....*....|...
gi 45708770  88 AFVLVYDICSPDSFDYVKALRQR 110
Cdd:cd01892  80 VACLVYDSSDPNSFSYCAEVYKK 102

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDgPRLYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQD 85
Cdd:cd04137   3 KIAVLGSRSVGKSSLTVQFVEGHFVESYYPTI-ENTFSKIITYKGQEYHLEIVD---------TAGQDEYSILPQKYSIG 72

                        90       100
                ....*....|....*....|....*.
gi 45708770  86 TDAFVLVYDICSPDSFDYVKALRQRI 111
Cdd:cd04137  73 IHGYILVYSVTSRKSFEVVKVIYDKI 98

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSL 83
Cdd:cd04141   4 KIVMLGAGGVGKSAVTMQFISHSFPDYHDPTieDA---YKTQARIDNEPALLDILD---------TAGQAEFTAMRDQYM 71

                        90       100       110
                ....*....|....*....|....*....|..
gi 45708770  84 QDTDAFVLVYDICSPDSFDYVKALRQRIAETR 115
Cdd:cd04141  72 RCGEGFIICYSVTDRHSFQEASEFKELITRVR 103

Rab GTPase family 23 (Rab23)-like; Rab23-like subfamily. Rab23 is a member of the Rab family of small GTPases. In mouse, Rab23 has been shown to function as a negative regulator in the sonic hedgehog (Shh) signaling pathway. Rab23 mediates the activity of Gli2 and Gli3, transcription factors that regulate Shh signaling in the spinal cord, primarily by preventing Gli2 activation in the absence of Shh ligand. Rab23 also regulates a step in the cytoplasmic signal transduction pathway that mediates the effect of Smoothened (one of two integral membrane proteins that are essential components of the Shh signaling pathway in vertebrates). In humans, Rab23 is expressed in the retina. Mice contain an isoform that shares 93% sequence identity with the human Rab23 and an alternative splicing isoform that is specific to the brain. This isoform causes the murine open brain phenotype, indicating it may have a role in the development of the central nervous system. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAgpgsspgGPEEWPDAKDWSLQ 84
Cdd:cd04106   1 IKVIVVGNGNVGKSSMIQRFVKGIFTKDYKKTIGVDFLEKQIFLRQSDEDVRLMLWDTA-------GQEEFDAITKAYYR 73

                        90       100
                ....*....|....*....|....*....
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALRQRIAE 113
Cdd:cd04106  74 GAQACILVFSTTDRESFEAIESWKEKVEA 102

Ras homolog family, member G (RhoG) of small guanosine triphosphatases (GTPases); RhoG is a GTPase with high sequence similarity to members of the Rac subfamily, including the regions involved in effector recognition and binding. However, RhoG does not bind to known Rac1 and Cdc42 effectors, including proteins containing a Cdc42/Rac interacting binding (CRIB) motif. Instead, RhoG interacts directly with Elmo, an upstream regulator of Rac1, in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1. The RhoG-Elmo-Dock180 pathway is required for activation of Rac1 and cell spreading mediated by integrin, as well as for neurite outgrowth induced by nerve growth factor. Thus RhoG activates Rac1 through Elmo and Dock180 to control cell morphology. RhoG has also been shown to play a role in caveolar trafficking and has a novel role in signaling the neutrophil respiratory burst stimulated by G protein-coupled receptor (GPCR) agonists. 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 45708770   4 SLRVAVLGAPGVGKTAIIRQFLFGDYPERHRPT--DGprlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDW 81
Cdd:cd01875   3 SIKCVVVGDGAVGKTCLLICYTTNAFPKEYIPTvfDN---YSAQTAVDGRTVSLNLWD---------TAGQEEYDRLRTL 70

                        90       100
                ....*....|....*....|....
gi 45708770  82 SLQDTDAFVLVYDICSPDSFDYVK 105
Cdd:cd01875  71 SYPQTNVFIICFSIASPSSYENVR 94

Rnd3/RhoE/Rho8 GTPases; Rnd3/RhoE/Rho8 subfamily. Rnd3/RhoE/Rho8 is a member of the novel Rho subfamily Rnd, together with Rnd1/Rho6 and Rnd2/Rho7. Rnd3/RhoE is known to bind the serine-threonine kinase ROCK I. Unphosphorylated Rnd3/RhoE associates primarily with membranes, but ROCK I-phosphorylated Rnd3/RhoE localizes in the cytosol. Phosphorylation of Rnd3/RhoE correlates with its activity in disrupting RhoA-induced stress fibers and inhibiting Ras-induced fibroblast transformation. In cells that lack stress fibers, such as macrophages and monocytes, Rnd3/RhoE induces a redistribution of actin, causing morphological changes in the cell. In addition, Rnd3/RhoE has been shown to inhibit cell cycle progression in G1 phase at a point upstream of the pRb family pocket protein checkpoint. Rnd3/RhoE has also been shown to inhibit Ras- and Raf-induced fibroblast transformation. In mammary epithelial tumor cells, Rnd3/RhoE regulates the assembly of the apical junction complex and tight junction formation. Rnd3/RhoE is underexpressed in prostate cancer cells both in vitro and in vivo; re-expression of Rnd3/RhoE suppresses cell cycle progression and increases apoptosis, suggesting it may play a role in tumor suppression. 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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRlYRPAVLLDGAVYDLSIRDgdvagpgsSPGGPeEWPDAKDWSLQD 85
Cdd:cd04172   7 KIVVVGDSQCGKTALLHVFAKDCFPENYVPTVFEN-YTASFEIDTQRIELSLWD--------TSGSP-YYDNVRPLSYPD 76

                        90
                ....*....|....*....
gi 45708770  86 TDAFVLVYDICSPDSFDYV 104
Cdd:cd04172  77 SDAVLICFDISRPETLDSV 95

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770   5 LRVAVLGAPGVGKTAIIrQFLFGD---YPERHRPTDGPRLYRPAVLLDGAVYDLSIRDGDVAgpgsspgGPEEWPDAKDW 81
Cdd:cd04101   1 AQCAVVGDPAVGKSALV-QMFHSDgatFQKNYTMTTGCDLVVKTVPVPDTSDSVELFIFDSA-------GQELFSDMVEN 72

                        90       100
                ....*....|....*....|.
gi 45708770  82 SLQDTDAFVLVYDICSPDSFD 102
Cdd:cd04101  73 VWEQPAVVCVVYDVTNEVSFN 93

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 45708770   4 SLRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRlYRPAVLL-DGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWS 82
Cdd:cd04132   3 KVKIVVVGDGGCGKTCLLMVYAQGSFPEEYVPTVFEN-YVTTLQVpNGKIIELALWD---------TAGQEDYDRLRPLS 72

                        90       100
                ....*....|....*....|...
gi 45708770  83 LQDTDAFVLVYDICSPDSFDYVK 105
Cdd:cd04132  73 YPDVDVILICYSVDNPTSLDNVE 95

Rho GTPase TC10 (Tc10); TC10 is a Rho family protein that has been shown to induce microspike formation and neurite outgrowth in vitro. Its expression changes dramatically after peripheral nerve injury, suggesting an important role in promoting axonal outgrowth and regeneration. TC10 regulates translocation of insulin-stimulated GLUT4 in adipocytes and has also been shown to bind directly to Golgi COPI coat proteins. GTP-bound TC10 in vitro can bind numerous potential effectors. Depending on its subcellular localization and distinct functional domains, TC10 can differentially regulate two types of filamentous actin in adipocytes. TC10 mRNAs are highly expressed in three types of mouse muscle tissues: leg skeletal muscle, cardiac muscle, and uterus; they were also present in brain, with higher levels in adults than in newborns. TC10 has also been shown to play a role in regulating the expression of cystic fibrosis transmembrane conductance regulator (CFTR) through interactions with CFTR-associated ligand (CAL). The GTP-bound form of TC10 directs the trafficking of CFTR from the juxtanuclear region to the secretory pathway toward the plasma membrane, away from CAL-mediated DFTR degradation in the lysosome. 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 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQ 84
Cdd:cd04135   1 LKCVVVGDGAVGKTCLLMSYANDAFPEEYVPTVFDH-YAVSVTVGGKQYLLGLYD---------TAGQEDYDRLRPLSYP 70

                        90       100
                ....*....|....*....|.
gi 45708770  85 DTDAFVLVYDICSPDSFDYVK 105
Cdd:cd04135  71 MTDVFLICFSVVNPASFQNVK 91

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 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGPRlYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQD 85
Cdd:cd04131   3 KIVLVGDSQCGKTALLQVFAKDSFPENYVPTVFEN-YTASFEVDKQRIELSLWD---------TSGSPYYDNVRPLSYPD 72

                        90       100       110
                ....*....|....*....|....*....|
gi 45708770  86 TDAFVLVYDICSPDSFDYVkaLRQRIAETR 115
Cdd:cd04131  73 SDAVLICFDISRPETLDSV--LKKWKGEVR 100

GTPase SAR1 family domain [General function prediction only];

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 45708770   3 GSLRVAVLGAPGVGKTAIIRQFLfGDY--PERHRPTDGPRLYRPAVLLDGAVYDLSIRD 59
Cdd:COG1100   2 GEKKIVVVGTGGVGKTSLVNRLV-GDIfsLEKYLSTNGVTIDKKELKLDGLDVDLVIWD 59

Rab GTPase family 26 (Rab26); Rab26 subfamily. First identified in rat pancreatic acinar cells, Rab26 is believed to play a role in recruiting mature granules to the plasma membrane upon beta-adrenergic stimulation. Rab26 belongs to the Rab functional group III, which are considered key regulators of intracellular vesicle transport during exocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45708770   6 RVAVLGAPGVGKTAIIRQFLFGDY-PERHRPTDGPRLYRPAVLLDGAVYDLSIRDgdvagpgssPGGPEEWPDAKDWSLQ 84
Cdd:cd04112   2 KVMLVGDSGVGKTCLLVRFKDGAFlAGSFIATVGIQFTNKVVTVDGVKVKLQIWD---------TAGQERFRSVTHAYYR 72

                        90       100
                ....*....|....*....|....*....
gi 45708770  85 DTDAFVLVYDICSPDSFDYVKALRQRIAE 113
Cdd:cd04112  73 DAHALLLLYDVTNKSSFDNIRAWLTEILE 101

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 45708770   5 LRVAVLGAPGVGKTAIIRQFLFGDYPERHRPTDGprlyrpavlLDGAVYDLSIRDGDVAGPGSSPGGPEEWPDAKDWSLQ 84
Cdd:cd04119   1 IKVISMGNSGVGKSCIIKRYCEGRFVSKYLPTIG---------IDYGVKKVSVRNKEVRVNFFDLSGHPEYLEVRNEFYK 71

                        90       100
                ....*....|....*....|....*....
gi 45708770  85 DTDAFVLVYDICSPDSFDyvkALRQRIAE 113
Cdd:cd04119  72 DTQGVLLVYDVTDRQSFE---ALDSWLKE 97

Mitochondrial Rho family 1 (Miro1), N-terminal; Miro1 subfamily. Miro (mitochondrial Rho) proteins have tandem GTP-binding domains separated by a linker region containing putative calcium-binding EF hand motifs. Genes encoding Miro-like proteins were found in several eukaryotic organisms. This CD represents the N-terminal GTPase domain of Miro proteins. These atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. Most Rho proteins contain a lipid modification site at the C-terminus; however, Miro is one of few Rho subfamilies that lack this feature.

                        10        20
                ....*....|....*....|....*...
gi 45708770   4 SLRVAVLGAPGVGKTAIIRQFLFGDYPE 31
Cdd:cd01893   2 DVRIVLIGDEGVGKSSLIMSLVSEEFPE 29