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 1907172309   1 MEILDTAGQ---EDTIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKK-PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd04146    49 LEIQDTPGQqqnEDPESLERSLRWADGFVLVYSITDRSSFDVVSQLLQLIREIKKrDGEIPVILVGNKADLLHSRQVSTE 128

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  77 EGEKLATELACAFYECSACTGEGNITEVFYELCREVRR 114
Cdd:cd04146   129 EGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

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 1907172309   1 MEILDTAGQ---EDTIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKK-PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd04146    49 LEIQDTPGQqqnEDPESLERSLRWADGFVLVYSITDRSSFDVVSQLLQLIREIKKrDGEIPVILVGNKADLLHSRQVSTE 128

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  77 EGEKLATELACAFYECSACTGEGNITEVFYELCREVRR 114
Cdd:cd04146   129 EGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

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 1907172309   1 MEILDTAGQE--DTIqREGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVK--KPKNVTLILVGNKADLDHSRQVSTE 76
Cdd:pfam00071  50 LQIWDTAGQErfRAL-RPLYYRGADGFLLVYDITSRDSFENV---KKWVEEILrhADENVPIVLVGNKCDLEDQRVVSTE 125

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYELCREVRR 114
Cdd:pfam00071 126 EGEALAKELGLPFMETSAKTNE-NVEEAFEELAREILK 162

GTPase SAR1 family domain [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   2 EILDTAGQEdtIQREGHMRWGE------GFVLVYDITDRGSFE-EVLPLKNILdevKKPKNVTLILVGNKADLDHSRQVS 74
Cdd:COG1100    56 VIWDTPGQD--EFRETRQFYARqltgasLYLFVVDGTREETLQsLYELLESLR---RLGKKSPIILVLNKIDLYDEEEIE 130

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1907172309  75 TEEG--EKLATELACAFYECSACTGEGnITEVFYELCREVRR 114
Cdd:COG1100   131 DEERlkEALSEDNIVEVVATSAKTGEG-VEELFAALAEILRG 171

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 1907172309   1 MEILDTAGQ---EDTIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKK-PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd04146    49 LEIQDTPGQqqnEDPESLERSLRWADGFVLVYSITDRSSFDVVSQLLQLIREIKKrDGEIPVILVGNKADLLHSRQVSTE 128

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  77 EGEKLATELACAFYECSACTGEGNITEVFYELCREVRR 114
Cdd:cd04146   129 EGQKLALELGCLFFEVSAAENYLEVQNVFHELCREVRR 166

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 1907172309    1 MEILDTAGQED-TIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:smart00010  52 LDILDTAGQEEfSAMRDQYMRTGEGFLLVYSITDRQSFEEIAKFREQILRVKDRDDVPIVLVGNKCDLENERVVSTEEGK 131

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 1907172309   80 KLATELACAFYECSACTGEgNITEVFYELCREVRRR 115
Cdd:smart00010 132 ELARQWGCPFLETSAKERI-NVDEAFYDLVREIRKS 166

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 1907172309   1 MEILDTAGQE--DTIqREGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVK--KPKNVTLILVGNKADLDHSRQVSTE 76
Cdd:pfam00071  50 LQIWDTAGQErfRAL-RPLYYRGADGFLLVYDITSRDSFENV---KKWVEEILrhADENVPIVLVGNKCDLEDQRVVSTE 125

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYELCREVRR 114
Cdd:pfam00071 126 EGEALAKELGLPFMETSAKTNE-NVEEAFEELAREILK 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 1907172309   1 MEILDTAGQE--DTIQREgHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVKK--PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd00154    51 LQIWDTAGQErfRSITSS-YYRGAHGAILVYDVTNRESFENL---DKWLNELKEyaPPNIPIILVGNKSDLEDERQVSTE 126

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYELCR 110
Cdd:cd00154   127 EAQQFAKENGLLFFETSAKTGE-NVDEAFESLAR 159

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 1907172309   1 MEILDTAGQ-EDTIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04141    52 LDILDTAGQaEFTAMRDQYMRCGEGFIICYSVTDRHSFQEASEFKELITRVRLTEDIPLVLVGNKVDLEQQRQVTTEEGR 131

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  80 KLATELACAFYECSACTgEGNITEVFYELCREVRRRRM 117
Cdd:cd04141   132 NLAREFNCPFFETSAAL-RFYIDDAFHGLVREIRRKES 168

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 1907172309   1 MEILDTAGQED-TIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04175    51 LEILDTAGTEQfTAMRDLYMKNGQGFVLVYSITAQSTFNDLQDLREQILRVKDTEDVPMILVGNKCDLEDERVVGKEQGQ 130

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907172309  80 KLATELACAFYECSAcTGEGNITEVFYELCREVRR 114
Cdd:cd04175   131 NLARQWGCAFLETSA-KAKINVNEIFYDLVRQINR 164

Rap2 family GTPase consists of Rap2a, Rap2b, and Rap2c; The Rap2 subgroup is part of the Rap subfamily of the Ras family. It consists of Rap2a, Rap2b, and Rap2c. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   1 MEILDTAGQED-TIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04176    51 LEILDTAGTEQfASMRDLYIKNGQGFIVVYSLVNQQTFQDIKPMRDQIVRVKGYEKVPIILVGNKVDLESEREVSSAEGR 130

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1907172309  80 KLATELACAFYECSAcTGEGNITEVFYELCREV 112
Cdd:cd04176   131 ALAEEWGCPFMETSA-KSKTMVNELFAEIVRQM 162

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 1907172309   1 MEILDTAGQED-TIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04177    51 LEILDTAGTEQfTAMRELYIKSGQGFLLVYSVTSEASLNELGELREQVLRIKDSDNVPMVLVGNKADLEDDRQVSREDGV 130

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1907172309  80 KLATELACA-FYECSACTgEGNITEVFYELCREVR 113
Cdd:cd04177   131 SLSQQWGNVpFYETSARK-RTNVDEVFIDLVRQII 164

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 1907172309   1 MEILDTAGQE--DTIQrEGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVKK--PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd01867    54 LQIWDTAGQErfRTIT-TSYYRGAMGIILVYDITDEKSFENI---KNWMRNIDEhaSEDVERMLVGNKCDMEEKRVVSKE 129

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYELCREVRRR 115
Cdd:cd01867   130 EGEALAREYGIKFLETSAKANI-NVEEAFLTLAKDILKK 167

Rab-related GTPase family includes Rab5 and Rab22; regulates early endosome fusion; The Rab5-related subfamily includes Rab5 and Rab22 of mammals, Ypt51/Ypt52/Ypt53 of yeast, and RabF of plants. The members of this subfamily are involved in endocytosis and endocytic-sorting pathways. In mammals, Rab5 GTPases localize to early endosomes and regulate fusion of clathrin-coated vesicles to early endosomes and fusion between early endosomes. In yeast, Ypt51p family members similarly regulate membrane trafficking through prevacuolar compartments. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   2 EILDTAGQEdtiqRE---GHM--RWGEGFVLVYDITDRGSFEEvlpLKNILDEVKK--PKNVTLILVGNKADLDHSRQVS 74
Cdd:cd01860    53 EIWDTAGQE----RYrslAPMyyRGAAAAIVVYDITSEESFEK---AKSWVKELQEhgPPNIVIALAGNKADLESKRQVS 125

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  75 TEEGEKLATELACAFYECSACTGEgNITEVFYELCREV 112
Cdd:cd01860   126 TEEAQEYADENGLLFMETSAKTGE-NVNELFTEIARKL 162

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 1907172309   1 MEILDTAGQEDTIQREGH-MRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04148    51 LVVYDHWEQEDGMWLEDScMQVGDAYVIVYSVTDRSSFEKASELRIQLRRARQAEDIPIILVGNKSDLVRSREVSVQEGR 130

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1907172309  80 KLATELACAFYECSAcTGEGNITEVFYELCREVR-RRRMVQGKTRRRSST 128
Cdd:cd04148   131 ACAVVFDCKFIETSA-ALQHNVDELFEGIVRQVRlRRDSKEKNTRRMASR 179

Rab GTPase family 11 (Rab11)-like includes Rab11a, Rab11b, and Rab25; Rab11a, Rab11b, and Rab25 are closely related, evolutionary conserved Rab proteins that are differentially expressed. Rab11a is ubiquitously synthesized, Rab11b is enriched in brain and heart and Rab25 is only found in epithelia. Rab11/25 proteins seem to regulate recycling pathways from endosomes to the plasma membrane and to the trans-Golgi network. Furthermore, Rab11a is thought to function in the histamine-induced fusion of tubulovesicles containing H+, K+ ATPase with the plasma membrane in gastric parietal cells and in insulin-stimulated insertion of GLUT4 in the plasma membrane of cardiomyocytes. Overexpression of Rab25 has recently been observed in ovarian cancer and breast cancer, and has been correlated with worsened outcomes in both diseases. In addition, Rab25 overexpression has also been observed in prostate cancer, transitional cell carcinoma of the bladder, and invasive breast tumor cells. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   3 ILDTAGQEdtiqR-----EGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVKK--PKNVTLILVGNKADLDHSRQVST 75
Cdd:cd01868    56 IWDTAGQE----RyraitSAYYRGAVGALLVYDITKKSTFENV---ERWLKELRDhaDSNIVIMLVGNKSDLRHLRAVPT 128

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1907172309  76 EEGEKLATELACAFYECSACTGEgNITEVFYEL 108
Cdd:cd01868   129 EEAKAFAEKNGLSFIETSALDGT-NVEEAFKQL 160

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 1907172309   1 MEILDTAGQEdtiqR-----EGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVK--KPKNVTLILVGNKADLDHSRQV 73
Cdd:cd01861    51 LQLWDTAGQE----RfrsliPSYIRDSSVAVVVYDITNRQSFDNT---DKWIDDVRdeRGNDVIIVLVGNKTDLSDKRQV 123

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1907172309  74 STEEGEKLATELACAFYECSACTGEgNITEVF 105
Cdd:cd01861   124 STEEGEKKAKENNAMFIETSAKAGH-NVKQLF 154

Rab GTPase family 39 (Rab39); Found in eukaryotes, Rab39 is mainly found in epithelial cell lines, but is distributed widely in various human tissues and cell lines. It is believed to be a novel Rab protein involved in regulating Golgi-associated vesicular transport during cellular endocytosis. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   1 MEILDTAGQED--TIQReGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVK---KPKNVTLILVGNKADLDHSRQVST 75
Cdd:cd04111    54 LQLWDTAGQERfrSITR-SYYRNSVGVLLVFDITNRESFEHV---HDWLEEARshiQPHRPVFILVGHKCDLESQRQVTR 129

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1907172309  76 EEGEKLATELACAFYECSACTGEgNITEVFYELCREVRRR 115
Cdd:cd04111   130 EEAEKLAKDLGMKYIETSARTGD-NVEEAFELLTQEIYER 168

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 1907172309   1 MEILDTAG--QEDTIQREGHMRwGEGFVLVYDITDRGSFEEVLPLKNILDEVK--KPKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd04140    51 LQITDTTGshQFPAMQRLSISK-GHAFILVYSITSKQSLEELKPIYELICEIKgnNLEKIPIMLVGNKCDESPSREVSSS 129

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYEL 108
Cdd:cd04140   130 EGAALARTWNCAFMETSAKTNH-NVQELFQEL 160

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 1907172309   1 MEILDTAGQ-EDTIQREGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPKNVTLILVGNKADLDHSRQVSTEEGE 79
Cdd:cd04147    49 IDILDTSGSySFPAMRKLSIQNGDAFALVYSVDDPESFEEVKRLREEILEVKEDKFVPIVVVGNKIDSLAERQVEAADAL 128

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309  80 KLAT-ELACAFYECSACTGEgNITEVFYELCREV-----------RRRRMVQGKTRRRSS 127
Cdd:cd04147   129 STVElDWNNGFVEASAKDNE-NVTEVFKELLQQAnlpswlspalrRRRESAPSEIQRRPP 187

Rab GTPase family 4 (Rab4); Rab4 subfamily. Rab4 has been implicated in numerous functions within the cell. It helps regulate endocytosis through the sorting, recycling, and degradation of early endosomes. Mammalian Rab4 is involved in the regulation of many surface proteins including G-protein-coupled receptors, transferrin receptor, integrins, and surfactant protein A. Experimental data implicate Rab4 in regulation of the recycling of internalized receptors back to the plasma membrane. It is also believed to influence receptor-mediated antigen processing in B-lymphocytes, in calcium-dependent exocytosis in platelets, in alpha-amylase secretion in pancreatic cells, and in insulin-induced translocation of Glut4 from internal vesicles to the cell surface. Rab4 is known to share effector proteins with Rab5 and Rab11. 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 1907172309   1 MEILDTAGQED--TIQREgHMRWGEGFVLVYDITDRGSFEevlPLKNILDEVKK--PKNVTLILVGNKADLDHSRQVSTE 76
Cdd:cd04113    51 LQIWDTAGQERfrSVTRS-YYRGAAGALLVYDITSRESFN---ALTNWLTDARTlaSPDIVIILVGNKKDLEDDREVTFL 126

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1907172309  77 EGEKLATELACAFYECSACTGEgNITEVFYELCREV 112
Cdd:cd04113   127 EASRFAQENGLLFLETSALTGE-NVEEAFLKCARSI 161

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 1907172309  23 EGFVLVYDITDRGSFEEvlpLKNILDEVKK-------PKNVTLILVGNKADLDHSRQVSTEEGEKLATELACAFYECSAC 95
Cdd:cd04119    74 QGVLLVYDVTDRQSFEA---LDSWLKEMKQeggphgnMENIVVVVCANKIDLTKHRAVSEDEGRLWAESKGFKYFETSAC 150

                          90
                  ....*....|....*..
gi 1907172309  96 TGEGnITEVFYELCREV 112
Cdd:cd04119   151 TGEG-VNEMFQTLFSSI 166

Rab GTPase family 14 (Rab14); Rab14 GTPases are localized to biosynthetic compartments, including the rough ER, the Golgi complex, and the trans-Golgi network, and to endosomal compartments, including early endosomal vacuoles and associated vesicles. Rab14 is believed to function in both the biosynthetic and recycling pathways between the Golgi and endosomal compartments. Rab14 has also been identified on GLUT4 vesicles, and has been suggested to help regulate GLUT4 translocation. In addition, Rab14 is believed to play a role in the regulation of 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 1907172309   1 MEILDTAGQED--TIQReGHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEVKKPkNVTLILVGNKADLDHSRQVSTEEG 78
Cdd:cd04122    53 LQIWDTAGQERfrAVTR-SYYRGAAGALMVYDITRRSTYNHLSSWLTDARNLTNP-NTVIFLIGNKADLEAQRDVTYEEA 130

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1907172309  79 EKLATELACAFYECSACTGEgNITEVFYELCREV 112
Cdd:cd04122   131 KQFADENGLLFLECSAKTGE-NVEDAFLETAKKI 163

Ras homolog enriched in striatum (Rhes) and activator of G-protein signaling 1 (Dexras1/AGS1); This subfamily includes Rhes (Ras homolog enriched in striatum) and Dexras1/AGS1 (activator of G-protein signaling 1). These proteins are homologous, but exhibit significant differences in tissue distribution and subcellular localization. Rhes is found primarily in the striatum of the brain, but is also expressed in other areas of the brain, such as the cerebral cortex, hippocampus, inferior colliculus, and cerebellum. Rhes expression is controlled by thyroid hormones. In rat PC12 cells, Rhes is farnesylated and localizes to the plasma membrane. Rhes binds and activates PI3K, and plays a role in coupling serpentine membrane receptors with heterotrimeric G-protein signaling. Rhes has recently been shown to be reduced under conditions of dopamine supersensitivity and may play a role in determining dopamine receptor sensitivity. Dexras1/AGS1 is a dexamethasone-induced Ras protein that is expressed primarily in the brain, with low expression levels in other tissues. Dexras1 localizes primarily to the cytoplasm, and is a critical regulator of the circadian master clock to photic and nonphotic input. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907172309   1 MEILDTAGQED-TIQREGHMRWGEGFVLVYDITDRGSFEEVLPLK-NILD-------EVKKPKNVTLILVGNKADLDHSR 71
Cdd:cd04143    50 LDILDTSGNHPfPAMRRLSILTGDVFILVFSLDNRESFEEVCRLReQILEtksclknKTKENVKIPMVICGNKADRDFPR 129

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1907172309  72 QVSTEEGEKL-ATELACAFYECSACTGEgNITEVFYEL 108
Cdd:cd04143   130 EVQRDEVEQLvGGDENCAYFEVSAKKNS-NLDEMFRAL 166

Rab GTPase family 3 contains Rab3A, Rab3B, Rab3C and Rab3D; The Rab3 subfamily contains Rab3A, Rab3B, Rab3C, and Rab3D. All four isoforms were found in mouse brain and endocrine tissues, with varying levels of expression. Rab3A, Rab3B, and Rab3C localized to synaptic and secretory vesicles; Rab3D was expressed at high levels only in adipose tissue, exocrine glands, and the endocrine pituitary, where it is localized to cytoplasmic secretory granules. Rab3 appears to control Ca2+-regulated exocytosis. The appropriate GDP/GTP exchange cycle of Rab3A is required for Ca2+-regulated exocytosis to occur, and interaction of the GTP-bound form of Rab3A with effector molecule(s) is widely believed to be essential for this process. Functionally, most studies point toward a role for Rab3 in the secretion of hormones and neurotransmitters. 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 1907172309   1 MEILDTAGQED--TIQrEGHMRWGEGFVLVYDITDRGSFEEVlplKNILDEVKKPK--NVTLILVGNKADLDHSRQVSTE 76
Cdd:cd01865    52 LQIWDTAGQERyrTIT-TAYYRGAMGFILMYDITNEESFNAV---QDWSTQIKTYSwdNAQVILVGNKCDMEDERVVSAE 127

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1907172309  77 EGEKLATELACAFYECSAcTGEGNITEVFYEL 108
Cdd:cd01865   128 RGRQLADQLGFEFFEASA-KENINVKQVFERL 158

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 1907172309   1 MEILDTAGQED--TIQREgHMRWGEGFVLVYDITDRGSFEEVLPLKNILDEvkKPKNVTLILVGNKADLDHSRQVSTEEG 78
Cdd:cd04121    57 LQLWDTSGQGRfcTIFRS-YSRGAQGIILVYDITNRWSFDGIDRWIKEIDE--HAPGVPKILVGNRLHLAFKRQVATEQA 133

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1907172309  79 EKLATELACAFYECSA-CTgeGNITEVFYELCREVRRRrmvQGKTRRRSST 128
Cdd:cd04121   134 QAYAERNGMTFFEVSPlCN--FNITESFTELARIVLMR---HGRPPQSPPQ 179