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
                 ....*....|....*....|....*....|....*....|.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKTVSEESETQPLVALVG 66
Cdd:cd04109   76 AVCLVYDITNSQSFENLEDWLSVVKKVNEESETKPKMVLVG 116

Rab GTPase family 28 (Rab28); Rab28 subfamily. First identified in maize, Rab28 has been shown to be a late embryogenesis-abundant (Lea) protein that is regulated by the plant hormone abcisic acid (ABA). In Arabidopsis, Rab28 is expressed during embryo development and is generally restricted to provascular tissues in mature embryos. Unlike maize Rab28, it is not ABA-inducible. Characterization of the human Rab28 homolog revealed two isoforms, which differ by a 95-base pair insertion, producing an alternative sequence for the 30 amino acids at the C-terminus. The two human isoforms are presumably the result of alternative splicing. Since they differ at the C-terminus but not in the GTP-binding region, they are predicted to be targeted to different cellular locations. 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
                 ....*....|....*....|....*....|....*....|.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKTVSEESETQPLVALVG 66
Cdd:cd04109   76 AVCLVYDITNSQSFENLEDWLSVVKKVNEESETKPKMVLVG 116

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

                           10        20
                   ....*....|....*....|
gi 148705627    26 GILLVYDITNYQSFENLEDW 45
Cdd:smart00175  75 GALLVYDITNRESFENLENW 94

Rab GTPase family 28 (Rab28); Rab28 subfamily. First identified in maize, Rab28 has been shown to be a late embryogenesis-abundant (Lea) protein that is regulated by the plant hormone abcisic acid (ABA). In Arabidopsis, Rab28 is expressed during embryo development and is generally restricted to provascular tissues in mature embryos. Unlike maize Rab28, it is not ABA-inducible. Characterization of the human Rab28 homolog revealed two isoforms, which differ by a 95-base pair insertion, producing an alternative sequence for the 30 amino acids at the C-terminus. The two human isoforms are presumably the result of alternative splicing. Since they differ at the C-terminus but not in the GTP-binding region, they are predicted to be targeted to different cellular locations. 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
                 ....*....|....*....|....*....|....*....|.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKTVSEESETQPLVALVG 66
Cdd:cd04109   76 AVCLVYDITNSQSFENLEDWLSVVKKVNEESETKPKMVLVG 116

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
                 ....*....|....*....|....*....|....*...
gi 148705627  29 LVYDITNYQSFENLEDWYsvvKTVSEESETQPLVALVG 66
Cdd:cd01861   78 VVYDITNRQSFDNTDKWI---DDVRDERGNDVIIVLVG 112

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

                           10        20
                   ....*....|....*....|
gi 148705627    26 GILLVYDITNYQSFENLEDW 45
Cdd:smart00175  75 GALLVYDITNRESFENLENW 94

Rab GTPase family 12 (Rab12); Rab12 was first identified in canine cells, where it was localized to the Golgi complex. The specific function of Rab12 remains unknown, and inconsistent results about its cellular localization have been reported. More recent studies have identified Rab12 associated with post-Golgi vesicles, or with other small vesicle-like structures but not with the Golgi complex. 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. 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
                 ....*....|....*....|....*....|....*.
gi 148705627  23 SGKGILLVYDITNYQSFENLEDWYSVV-KTVSEESE 57
Cdd:cd04120   72 SAKGIILVYDITKKETFDDLPKWMKMIdKYASEDAE 107

Rab GTPase family 18 (Rab18); Rab18 subfamily. Mammalian Rab18 is implicated in endocytic transport and is expressed most highly in polarized epithelial cells. However, trypanosomal Rab, TbRAB18, is upregulated in the BSF (Blood Stream Form) stage and localized predominantly to elements of the Golgi complex. In human and mouse cells, Rab18 has been identified in lipid droplets, organelles that store neutral lipids. 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
                 ....*....|....*....|....*....|..
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKTVSEESE 57
Cdd:cd01863   75 GVILVYDVTRRDTFDNLDTWLNELDTYSTNPD 106

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
                 ....*....|....*....|....*....|....*....|.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKtvsEESETQPLVALVG 66
Cdd:cd01868   78 GALLVYDITKKSTFENVERWLKELR---DHADSNIVIMLVG 115

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
                 ....*....|....*....|....*....|....*....|.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKTVSEESetqPLVALVG 66
Cdd:cd01865   76 GFILMYDITNEESFNAVQDWSTQIKTYSWDN---AQVILVG 113

Rab GTPase family 7 (Rab7); Rab7 subfamily. Rab7 is a small Rab GTPase that regulates vesicular traffic from early to late endosomal stages of the endocytic pathway. The yeast Ypt7 and mammalian Rab7 are both involved in transport to the vacuole/lysosome, whereas Ypt7 is also required for homotypic vacuole fusion. Mammalian Rab7 is an essential participant in the autophagic pathway for sequestration and targeting of cytoplasmic components to the lytic compartment. Mammalian Rab7 is also proposed to function as a tumor suppressor. GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10
                 ....*....|....*...
gi 148705627  28 LLVYDITNYQSFENLEDW 45
Cdd:cd01862   77 VLVYDVTNPKSFESLDSW 94

Rab GTPase family 15 (Rab15); Rab15 colocalizes with the transferrin receptor in early endosome compartments, but not with late endosomal markers. It codistributes with Rab4 and Rab5 on early/sorting endosomes, and with Rab11 on pericentriolar recycling endosomes. It is believed to function as an inhibitory GTPase that regulates distinct steps in early endocytic 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
                 ....*....|....*....|....*....|....*...
gi 148705627  25 KGILLVYDITNYQSFENLEDWYSVVKTVSEESETQPLV 62
Cdd:cd04117   74 QGIFLVYDISSERSYQHIMKWVSDVDEYAPEGVQKILI 111

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
                 ....*....|....*....|....*.
gi 148705627  26 GILLVYDITNYQSFENLEDWYSVVKT 51
Cdd:cd04127   89 GFLLMFDLTSEQSFLNVRNWMSQLQA 114

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
                   ....*....|....*....|....*....|....*....|....
gi 148705627    23 SGKGILLVYDITNYQSFENLEDWYSVVKTVsEESETQPLVaLVG 66
Cdd:smart00010  73 TGEGFLLVYSITDRQSFEEIAKFREQILRV-KDRDDVPIV-LVG 114

rab6; Provisional

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 148705627  28 LLVYDITNYQSFENLEDWysvVKTVSEESETQPLVALVG 66
Cdd:PTZ00099  57 IVVYDITNRQSFENTTKW---IQDILNERGKDVIIALVG 92

Ras GTPase family containing H-Ras,N-Ras and K-Ras4A/4B; H-Ras/N-Ras/K-Ras subfamily. H-Ras, N-Ras, and K-Ras4A/4B are the prototypical members of the Ras family. These isoforms generate distinct signal outputs despite interacting with a common set of activators and effectors, and are strongly associated with oncogenic progression in tumor initiation. Mutated versions of Ras that are insensitive to GAP stimulation (and are therefore constitutively active) are found in a significant fraction of human cancers. Many Ras guanine nucleotide exchange factors (GEFs) have been identified. They are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active (GTP-bound) Ras interacts with several effector proteins that stimulate a variety of diverse cytoplasmic signaling activities. Some are known to positively mediate the oncogenic properties of Ras, including Raf, phosphatidylinositol 3-kinase (PI3K), RalGEFs, and Tiam1. Others are proposed to play negative regulatory roles in oncogenesis, including RASSF and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 148705627  23 SGKGILLVYDITNYQSFENLEDWYSVVKTVsEESETQPLVaLVG 66
Cdd:cd04138   72 TGEGFLCVFAINSRKSFEDIHTYREQIKRV-KDSDDVPMV-LVG 113

Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases); The Ras family of the Ras superfamily includes classical N-Ras, H-Ras, and K-Ras, as well as R-Ras, Rap, Ral, Rheb, Rhes, ARHI, RERG, Rin/Rit, RSR1, RRP22, Ras2, Ras-dva, and RGK proteins. Ras proteins regulate cell growth, proliferation and differentiation. Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. Many RasGEFs have been identified. These are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. Active GTP-bound Ras interacts with several effector proteins: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs and NORE/MST1. Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. Due to the presence of truncated sequences in this CD, the lipid modification site is not available for annotation.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*
gi 148705627  22 TSGKGILLVYDITNYQSFENLEDWYSVVKTVSeESETQPLVaLVG 66
Cdd:cd00876   69 RNGDGFILVYSITSRESFEEIKNIREQILRVK-DKEDVPIV-LVG 111