ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   4 RERNKKRLLELLRAPdtGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFPDISRVKSVRLDFWDDSIVEFMIHNGNL 83
Cdd:cd08844     1 RDRNKKRLLELLKLP--GNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNL 78

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1092878774  84 RVKAKFEARVPAFYYIPQANDCLVLKEQWIRAKY 117
Cdd:cd08844    79 KAKAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 255 NYLKQGFMEKTGPK-KEPFKKRWFALDCheRRLLYYKNPLDAFEQGQVFLGNKEQGYEAYEDLPKGIRGnRWKAGLTIVT 333
Cdd:cd01251     1 DFLKEGYLEKTGPKqTDGFRKRWFTLDD--RRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1092878774 334 PERRFVLTCPSEKEQQEWLESLRGVLSS 361
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   4 RERNKKRLLELLRAPdtGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFPDISRVKSVRLDFWDDSIVEFMIHNGNL 83
Cdd:cd08844     1 RDRNKKRLLELLKLP--GNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNL 78

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1092878774  84 RVKAKFEARVPAFYYIPQANDCLVLKEQWIRAKY 117
Cdd:cd08844    79 KAKAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 255 NYLKQGFMEKTGPK-KEPFKKRWFALDCheRRLLYYKNPLDAFEQGQVFLGNKEQGYEAYEDLPKGIRGnRWKAGLTIVT 333
Cdd:cd01251     1 DFLKEGYLEKTGPKqTDGFRKRWFTLDD--RRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1092878774 334 PERRFVLTCPSEKEQQEWLESLRGVLSS 361
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

Putative GTP-ase activating proteins for the small GTPase, ARF; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   12 LELLRApDTGNAHCADCGAADPDWASYKLGIFICLNCCGVHRN-FPDISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFE 90
Cdd:smart00105   1 LKLLRS-IPGNKKCFDCGAPNPTWASVNLGVFLCIECSGIHRSlGVHISKVRSLTLDTWTEEELRLLQKGGNENANSIWE 79

                           90       100       110
                   ....*....|....*....|....*....|..
gi 1092878774   91 ARVPAFYYIPQANDCLVLKEQWIRAKYERREF 122
Cdd:smart00105  80 SNLDDFSLKPPDDDDQQKYESFIAAKYEEKLF 111

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   7 NKKRLLELLRApDTGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLDFWDDSIVEFMIHNGNLRV 85
Cdd:PLN03114    8 DKISVFKKLKA-KSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGvHISFVRSTNLDSWSSEQLKMMIYGGNNRA 86

                  ....*
gi 1092878774  86 KAKFE 90
Cdd:PLN03114   87 QVFFK 91

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 258 KQGFM-EKTGPKKEPFKKRWFALdcHERRLLYYKNPL---DAFEQGQVFLgnkeQGYEAYEDLPKGIRGNRWKAGLTIV- 332
Cdd:pfam00169   3 KEGWLlKKGGGKKKSWKKRYFVL--FDGSLLYYKDDKsgkSKEPKGSISL----SGCEVVEVVASDSPKRKFCFELRTGe 76

                          90       100
                  ....*....|....*....|....*....
gi 1092878774 333 -TPERRFVLTCPSEKEQQEWLESLRGVLS 360
Cdd:pfam00169  77 rTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  135 REGFLWKRGRD-NSQFLRRKFVLlaREGLLKYFTKEQ---GKSPKAVISIKDLNATFQTE--KIGHPHGLQITYRRDght 208
Cdd:smart00233   3 KEGWLYKKSGGgKKSWKKRYFVL--FNSTLLYYKSKKdkkSYKPKGSIDLSGCTVREAPDpdSSKKPHCFEIKTSDR--- 77

                           90       100
                   ....*....|....*....|...
gi 1092878774  209 RNLFVYHESGKEIVDWFNALRAA 231
Cdd:smart00233  78 KTLLLQAESEEEREKWVEALRKA 100

ADAP2 GTPase activating protein for Arf, with dual PH domains; The ADAP subfamily, ArfGAPs with dual pleckstrin homology (PH) domains, includes two members: ADAP1 and ADAP2. Both ADAP1 (also known as centaurin-alpha1, p42(IP4), or PIP3BP) and ADAP2 (centaurin-alpha2) display a GTPase-activating protein (GAP) activity toward Arf6 (ADP-ribosylation factor 6), which is involved in protein trafficking that regulates endocytic recycling, cytoskeleton remodeling, and neuronal differentiation. ADAP2 has high sequence similarity to the ADAP1 and they both contain a ArfGAP domain at the N-terminus, followed by two PH domains. However, ADAP1, unlike ADAP2, contains a putative N-terminal nuclear localization signal. The PH domains of ADAP1bind to the two second messenger molecules phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (I(1,3,4,5)P4) with identical high affinity, whereas those of ADAP2 specifically binds phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) and PI(3,4,5)P3, which are produced by activated phosphatidylinositol 3-kinase. ADAP1 is predominantly expressed in the brain neurons, while ADAP2 is broadly expressed, including the adipocytes, heart, and skeletal muscle but not in the brain. The limited distribution and high expression of ADAP1 in the brain indicates that ADAP1 is important for neuronal functions. ADAP1 has been shown to highly expressed in the neurons and plagues of Alzheimer's disease patients. In other hand, ADAP2 gene deletion has been shown to cause circulatory deficiencies and heart shape defects in zebrafish, indicating that ADAP2 has a vital role in heart development. Taken together, the hemizygous deletion of ADAP2 gene may be contributing to the cardiovascular malformation in patients with neurofibromatosis type 1 (NF1) microdeletions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   4 RERNKKRLLELLRAPdtGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFPDISRVKSVRLDFWDDSIVEFMIHNGNL 83
Cdd:cd08844     1 RDRNKKRLLELLKLP--GNSVCADCGAPDPDWASYTLGIFICLNCSGVHRNLPDISRVKSIRLDFWEDELVEFMKENGNL 78

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1092878774  84 RVKAKFEARVPAFYYIPQANDCLVLKEQWIRAKY 117
Cdd:cd08844    79 KAKAKFEAFVPPFYYRPQANDCDVLKEQWIRAKY 112

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 1; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the first PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 133 GNREGFLWKRGRDNSQFLRRKFVLLAREGLLKYFTKEQGKSPKAVISIKDLNATFQTEKIGHPHGLQITYRRDGHTRNLF 212
Cdd:cd13252     1 GSKEGFLWKRGKDNNQFKQRKFVLSEREGTLKYFVKEDAKEPKAVISIEELNATFQPEKIGHPNGLQITYLKDGSTRNIF 80

                          90       100
                  ....*....|....*....|....*....
gi 1092878774 213 VYHESGKEIVDWFNALRAARLQYLKMAFP 241
Cdd:cd13252    81 VYHEDGKEIVDWYNAIRAARLHYLQVAFP 109

ArfGAP with dual PH domains Pleckstrin homology (PH) domain, repeat 2; ADAP (also called centaurin alpha) is a phophatidlyinositide binding protein consisting of an N-terminal ArfGAP domain and two PH domains. In response to growth factor activation, PI3K phosphorylates phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 1 is recruited to the plasma membrane following growth factor stimulation by specific binding of its PH domain to phosphatidylinositol 3,4,5-trisphosphate. Centaurin alpha 2 is constitutively bound to the plasma membrane since it binds phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate with equal affinity. This cd contains the second PH domain repeat. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 255 NYLKQGFMEKTGPK-KEPFKKRWFALDCheRRLLYYKNPLDAFEQGQVFLGNKEQGYEAYEDLPKGIRGnRWKAGLTIVT 333
Cdd:cd01251     1 DFLKEGYLEKTGPKqTDGFRKRWFTLDD--RRLMYFKDPLDAFPKGEIFIGSKEEGYSVREGLPPGIKG-HWGFGFTLVT 77

                          90       100
                  ....*....|....*....|....*...
gi 1092878774 334 PERRFVLTCPSEKEQQEWLESLRGVLSS 361
Cdd:cd01251    78 PDRTFLLSAETEEERREWITAIQKVLER 105

Putative GTPase activating protein for Arf; Putative zinc fingers with GTPase activating proteins (GAPs) towards the small GTPase, Arf. The GAP of ARD1 stimulates GTPase hydrolysis for ARD1 but not ARFs.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   8 KKRLLELLRAPdtGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNLRVK 86
Cdd:pfam01412   1 KRVLRELLKLP--GNKVCADCGAPNPTWASVNLGIFICIDCSGVHRSLgVHISKVRSLTLDTWTDEQLELMKAGGNDRAN 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1092878774  87 AKFEARVPAFYYIPQaNDCLVLKEQWIRAKYERREFMADG 126
Cdd:pfam01412  79 EFWEANLPPSYKPPP-SSDREKRESFIRAKYVEKKFAKPG 117

Stromal membrane-associated proteins; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  11 LLELLRAPDtgNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKF 89
Cdd:cd08839     1 LAKLLREED--NKYCADCGAKGPRWASWNLGVFICIRCAGIHRNLgVHISKVKSVNLDSWTPEQVQSMQEMGNARANAYY 78

                          90       100
                  ....*....|....*....|....*...
gi 1092878774  90 EARVPAFYYIPQANDCLvlkEQWIRAKY 117
Cdd:cd08839    79 EANLPDGFRRPQTDSAL---ENFIRDKY 103

ArfGAP with GTPase domain, ANK repeat and PH domains; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  21 GNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFEARVPAfYYI 99
Cdd:cd08836    11 GNDHCVDCGAPNPDWASLNLGALMCIECSGIHRNLgTHISRVRSLDLDDWPVELLKVMSAIGNDLANSVWEGNTQG-RTK 89

                          90
                  ....*....|....*....
gi 1092878774 100 PQANDCLVLKEQWIRAKYE 118
Cdd:cd08836    90 PTPDSSREEKERWIRAKYE 108

Stromal membrane-associated protein 2; a subfamily of the ArfGAP family; The SMAP subfamily of Arf GTPase-activating proteins consists of the two structurally-related members, SMAP1 and SMAP2. Each SMAP member exhibits common and distinct functions in vesicle trafficking. They both bind to clathrin heavy chain molecules and are involved in the trafficking of clathrin-coated vesicles. SMAP1 preferentially exhibits GAP toward Arf6, while SMAP2 prefers Arf1 as a substrate. SMAP1 is involved in Arf6-dependent vesicle trafficking, but not Arf6-mediated actin cytoskeleton reorganization, and regulates clathrin-dependent endocytosis of the transferrin receptors and E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46 from the early endosome to the trans-Golgi network (TGN). SMAP2 has the Clathrin Assembly Lymphoid Myeloid (CALM)-binding domain, but SMAP1 does not.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  22 NAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFEARVPAFYYIP 100
Cdd:cd08859    10 NKFCADCQSKGPRWASWNIGVFICIRCAGIHRNLGvHISRVKSVNLDQWTQEQIQCMQEMGNGKANRLYEAFLPENFRRP 89

                          90       100
                  ....*....|....*....|.
gi 1092878774 101 QANDCLvlkEQWIRAKYERRE 121
Cdd:cd08859    90 QTDQAV---EGFIRDKYEKKK 107

ArfGAP with GTPase domain, ANK repeat and PH domain 3; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  21 GNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFEARVPAfYYI 99
Cdd:cd08855    13 GNSFCIDCDAPNPDWASLNLGALMCIECSGIHRNLgTHLSRVRSLDLDDWPVELSMVMTAIGNAMANSVWEGALDG-YSK 91

                          90
                  ....*....|....*....
gi 1092878774 100 PQANDCLVLKEQWIRAKYE 118
Cdd:cd08855    92 PGPDSTREEKERWIRAKYE 110

The GIT subfamily of ADP-ribosylation factor GTPase-activating proteins; The GIT (G-protein coupled receptor kinase-interacting protein) subfamily includes GIT1 and GIT2, which have three ANK repeats, a Spa-homology domain (SHD), a coiled-coil domain and a C-terminal paxillin-binding site (PBS). The GIT1/2 proteins are GTPase-activating proteins that function as an inactivator of Arf signaling, and interact with the PIX/Cool family of Rac/Cdc42 guanine nucleotide exchange factors (GEFs). Unlike other ArfGAPs, GIT and PIX (Pak-interacting exchange factor) proteins are tightly associated to form an oligomeric complex that acts as a scaffold and signal integrator that can be recruited for multiple signaling pathways. The GIT/PIX complex functions as a signaling scaffold by binding to specific protein partners. As a result, the complex is transported to specific cellular locations. For instance, the GIT partners paxillin or integrin-alpha4 (to focal adhesions), piccolo and liprin-alpha (to synapses), and the beta-PIX partner Scribble (to epithelial cell-cell contacts and synapses). Moreover, the GIT/PIT complex functions to integrate signals from multiple GTP-binding protein and protein kinase pathways to regulate the actin cytoskeleton and thus cell polarity, adhesion and migration.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  25 CADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFM--IHNGN--------LRVKAKFEARV 93
Cdd:cd08833    11 CADCSAPDPEWASINRGVLICDECCSIHRSLgRHISQVKSLRKDQWPPSLLEMVqtLGNNGansiwehsLLDPSQSGKRK 90

                          90       100
                  ....*....|....*....|....
gi 1092878774  94 PafyyiPQANDCLVLKEQWIRAKY 117
Cdd:cd08833    91 P-----IPPDPVHPTKEEFIKAKY 109

ArfGAP with GTPase domain, ANK repeat and PH domain 2; The AGAP subfamily of ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) includes three members: AGAP1-3. In addition to the Arf GAP domain, AGAP proteins contain GTP-binding protein-like, ANK repeat and pleckstrin homology (PH) domains. AGAP1 and AGAP2 have phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-mediated GTPase-activating protein (GAP) activity preferentially toward Arf1, and function in the endocytic system. AGAP1 and AGAP2 independently regulate AP-3 endosomes and AP-1/Rab4 fast recycling endosomes, respectively. AGAP1, via its PH domain, directly interacts with the adapter protein 3 (AP-3), which is a coat protein involved in trafficking in the endosomal-lysosomal system, and regulates AP-3-dependent trafficking. In other hand, AGAP2 specifically binds the clathrin adaptor protein AP-1 and regulates the AP-1/Rab-4 dependent endosomal trafficking. AGAP2 is overexpressed in different human cancers including prostate carcinoma and glioblastoma, and promotes cancer cell invasion. AGAP3 exists as a component of the NMDA receptor complex that regulates Arf6 and Ras/ERK signaling pathways. Moreover, AGAP3 regulates AMPA receptor trafficking through the ArfGAP domain. Together, AGAP3 is believed to involve in linking NMDA receptor activation to AMPA receptor trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  21 GNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFEARVPAfYYI 99
Cdd:cd08853    12 GNSHCVDCETQNPKWASLNLGVLMCIECSGIHRNLgTHLSRVRSLDLDDWPVELRKVMSSIGNELANSIWEGSSQG-QTK 90

                          90
                  ....*....|....*....
gi 1092878774 100 PQANDCLVLKEQWIRAKYE 118
Cdd:cd08853    91 PSSDSTREEKERWIRAKYE 109

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing proteins; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1092878774  21 GNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLD--FWDDSIVEFMIHNGNLRVKAKFEARVPA 95
Cdd:cd08837    12 ANRFCADCGAPDPDWASINLCVVICKQCAGEHRSLgSNISKVRSLKMDtkVWTEELVELFLKLGNDRANRFWAANLPP 89

Arf1 GTPase-activating protein 2/3-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   5 ERNKKrLLELLRAPDtgNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLDFWDDSIVEFMIHNGNL 83
Cdd:cd08831     1 ERDAI-FKKLRSKPE--NKVCFDCGAKNPTWASVTFGVFLCLDCSGVHRSLgVHISFVRSTNLDSWTPEQLRRMKVGGNA 77

                  ....*..
gi 1092878774  84 RVKAKFE 90
Cdd:cd08831    78 KAREFFK 84

ARF1 GTPase-activating protein 1-like; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   8 KKRLLELLRAPDtgNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLDFWDDSIVEFMIHNGNLRVK 86
Cdd:cd08959     2 RAVFKKLRSKPE--NKVCFDCGAKNPQWASVTYGIFICLDCSGVHRGLGvHISFVRSTTMDKWTEEQLRKMKVGGNANAR 79

                  ....*
gi 1092878774  87 AKFEA 91
Cdd:cd08959    80 EFFKQ 84

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 3; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP3 possesses a unique dual-specificity GAP activity for Arf6 and RhoA regulated by PI(3,4,5)P3 and a small GTPase Rap1-GTP. The RhoGAP activity of ARAP3 is enhanced by direct binding of Rap1-GTP to the Ras-association (RA) domain. ARAP3 is involved in regulation of cell shape and adhesion.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1092878774  22 NAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLD--FWDDSIVEFMIHNGNLRVKAKFEARVPA 95
Cdd:cd17902    13 NRFCADCHASSPDWASINLCVVICKQCAGQHRSLgSGISKVQSLKLDtsVWSNEIVQLFIVLGNDRANRFWAARLPA 89

ArfGAP domain of ASAP1 (ArfGAP with SH3 domain, ANK repeat and PH domain-containing protein 1); The ArfGAPs are a family of multidomain proteins with a common catalytic domain that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. ASAP-subfamily GAPs include three members: ASAP1, ASAP2, ASAP3. The ASAP subfamily comprises Arf GAP, SH3, ANK repeat and PH domains. From the N-terminus, each member has a BAR, PH, Arf GAP, ANK repeat, and proline rich domains. Unlike ASAP3, ASAP1 and ASAP2 also have an SH3 domain at the C-terminus. ASAP1 and ASAP2 show strong GTPase-activating protein (GAP) activity toward Arf1 and Arf5 and weak activity toward Arf6. ASAP1 is a target of Src and FAK signaling that regulates focal adhesions, circular dorsal ruffles (CDR), invadopodia, and podosomes. ASAP1 GAP activity is synergistically stimulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid. ASAP2 is believed to function as an ArfGAP that controls ARF-mediated vesicle budding when recruited to Golgi membranes. It also functions as a substrate and downstream target for protein tyrosine kinases Pyk2 and Src, a pathway that may be involved in the regulation of vesicular transport. ASAP3 is a focal adhesion-associated ArfGAP that functions in cell migration and invasion. Similar to ASAP1, the GAP activity of ASAP3 is strongly enhanced by PIP2 via PH domain. Like ASAP1, ASAP3 associates with focal adhesions and circular dorsal ruffles. However, unlike ASAP1, ASAP3 does not localize to invadopodia or podosomes. ASAP 1 and 3 have been implicated in oncogenesis, as ASAP1 is highly expressed in metastatic breast cancer and ASAP3 in hepatocellular carcinoma.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  13 ELLRAPdtGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLDFWDDSIVEFMIHNGNLRVKAKFEA 91
Cdd:cd08848     8 DVQRLP--GNEVCCDCGSPDPTWLSTNLGILTCIECSGIHREMGvHISRIQSLELDKLGTSELLLAKNVGNNSFNDIMEG 85

                          90       100       110
                  ....*....|....*....|....*....|.
gi 1092878774  92 RVPAFYYIPQANDCLVLKEQWIRAKYERREF 122
Cdd:cd08848    86 NLPSPSPKPSPSSDMTARKEYITAKYVEHRF 116

ArfGap with Rho-Gap domain, ANK repeat and PH domain-containing protein 1; The ARAP subfamily includes three members, ARAP1-3, and belongs to the ADP-ribosylation factor GTPase-activating proteins (Arf GAPs) family of proteins that promotes the hydrolysis of GTP bound to Arf, thereby inactivating Arf signaling. The function of Arfs is dependent on GAPs and guanine nucleotide exchange factors (GEFs), which allow Arfs to cycle between the GDP-bound and GTP-bound forms. In addition to the Arf GAP domain, ARAPs contain the SAM (sterile-alpha motif) domain, 5 pleckstrin homology (PH) domains, the Rho-GAP domain, the Ras-association domain, and ANK repeats. ARAPs show phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-dependent GAP activity toward Arf6. ARAPs play important roles in endocytic trafficking, cytoskeleton reorganization in response to growth factors stimulation, and focal adhesion dynamics. ARAP1 localizes to the plasma membrane, the Golgi complex, and endosomal compartments. It displays PI(3,4,5)P3-dependent ArfGAP activity that regulates Arf-, RhoA-, and Cdc42-dependent cellular events. For example, ARAP1 inhibits the trafficking of epidermal growth factor receptor (EGFR) to the early endosome.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1092878774  21 GNAHCADCGAADPDWASYKLGIFICLNCCGVHRNF-PDISRVKSVRLD--FWDDSIVEFMIHNGNLRVKAKFEARVP 94
Cdd:cd17901    12 SNRFCADCGSPKPDWASVNLCVVICKRCAGEHRGLgPSVSKVRSLKMDrkVWTEELIELFLLLGNGKANQFWAANVP 88

ADP-ribosylation factor GTPase-activating protein AGD10; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774   7 NKKRLLELLRApDTGNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLDFWDDSIVEFMIHNGNLRV 85
Cdd:PLN03114    8 DKISVFKKLKA-KSDNKICFDCNAKNPTWASVTYGIFLCIDCSAVHRSLGvHISFVRSTNLDSWSSEQLKMMIYGGNNRA 86

                  ....*
gi 1092878774  86 KAKFE 90
Cdd:PLN03114   87 QVFFK 91

Arf1 GTPase-activating protein 2; ArfGAP (ADP Ribosylation Factor GTPase Activating Protein) domain is a part of ArfGap1-like proteins that play a crucial role in controlling of membrane trafficking, particularly in the formation of COPI (coat protein complex I)-coated vesicles on Golgi membranes. The ArfGAP1 protein subfamily consists of three members: ArfGAP1 (Gcs1p in yeast), ArfGAP2 and ArfGAP3 (both are homologs of yeast Glo3p). ArfGAP2/3 are closely related, but with little similarity to ArfGAP1, except the catalytic ArfGAP domain. They promote hydrolysis of GTP bound to the small G protein ADP-ribosylation factor 1 (Arf1), which leads to the dissociation of coat proteins from Golgi-derived membranes and vesicles. Dissociation of the coat proteins is required for the fusion of these vesicles with target compartments. Thus, the GAP catalytic activity plays a key role in the formation of COPI vesicles from Golgi membrane. In contrast to ArfGAP1, which displays membrane curvature-dependent ArfGAP activity, ArfGAP2 and ArfGAP3 activities are dependent on coatomer (the core COPI complex) which required for efficient recruitment of ArfGAP2 and ArfGAP3 to the Golgi membrane. Accordingly, ArfGAP2/3 has been implicated in coatomer-mediated protein transport between the Golgi complex and the endoplasmic reticulum. Unlike ArfGAP1, which is controlled by membrane curvature through its amphipathic lipid packing sensor (ALPS) motifs, ArfGAP2/3 do not possess ALPS motif.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1092878774  11 LLELLRAPDTgNAHCADCGAADPDWASYKLGIFICLNCCGVHRNFP-DISRVKSVRLD 67
Cdd:cd09029     9 LFKRLRAIPT-NKACFDCGAKNPSWASITYGVFLCIDCSGVHRSLGvHLSFIRSTELD 65

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774  257 LKQGFMEK-TGPKKEPFKKRWFALdcHERRLLYYKNP---LDAFEQGQVFLgnkeQGYEAYEDLPKGIRGNRWkaGLTIV 332
Cdd:smart00233   2 IKEGWLYKkSGGGKKSWKKRYFVL--FNSTLLYYKSKkdkKSYKPKGSIDL----SGCTVREAPDPDSSKKPH--CFEIK 73

                           90       100
                   ....*....|....*....|....*....
gi 1092878774  333 TPERR-FVLTCPSEKEQQEWLESLRGVLS 360
Cdd:smart00233  74 TSDRKtLLLQAESEEEREKWVEALRKAIA 102

Pleckstrin homology (PH) domain containing, family H (with MyTH4 domain) members 1 and 2 (PLEKHH1) PH domain, repeat 1; PLEKHH1 and PLEKHH2 (also called PLEKHH1L) are thought to function in phospholipid binding and signal transduction. There are 3 Human PLEKHH genes: PLEKHH1, PLEKHH2, and PLEKHH3. There are many isoforms, the longest of which contain a FERM domain, a MyTH4 domain, two PH domains, a peroximal domain, a vacuolar domain, and a coiled coil stretch. The FERM domain has a cloverleaf tripart structure (FERM_N, FERM_M, FERM_C/N, alpha-, and C-lobe/A-lobe, B-lobe, C-lobe/F1, F2, F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 258 KQGFMEKTGPKKEPFKKRWFALdcHERRLLYYKNPLDafeqgqvfLGNKEQGYEAYEDLPKGIRGNRwKAGLTIVTPERR 337
Cdd:cd13282     1 KAGYLTKLGGKVKTWKRRWFVL--KNGELFYYKSPND--------VIRKPQGQIALDGSCEIARAEG-AQTFEIVTEKRT 69

                          90       100
                  ....*....|....*....|...
gi 1092878774 338 FVLTCPSEKEQQEWLESLRGVLS 360
Cdd:cd13282    70 YYLTADSENDLDEWIRVIQNVLR 92

TBC1 domain family member 2A pleckstrin homology (PH) domain; TBC1D2A (also called PARIS-1/Prostate antigen recognized and identified by SEREX 1 and ARMUS) contains a PH domain and a TBC-type GTPase catalytic domain. TBC1D2A integrates signaling between Arf6, Rac1, and Rab7 during junction disassembly. Activated Rac1 recruits TBC1D2A to locally inactivate Rab7 via its C-terminal TBC/RabGAP domain and facilitate E-cadherin degradation in lysosomes. The TBC1D2A PH domain mediates localization at cell-cell contacts and coprecipitates with cadherin complexes. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1092878774 256 YLkqGFMEKTGPKKEPFKKRWFALDchERR--LLYYKNPLDAFEQGQVFLGNKEQGYEAyeDLPKGIrgnrwkagLTIVT 333
Cdd:cd01265     5 YL--NKLETRGLGLKGWKRRWFVLD--ESKcqLYYYRSPQDATPLGSIDLSGAAFSYDP--EAEPGQ--------FEIHT 70

                          90       100
                  ....*....|....*....|..
gi 1092878774 334 PERRFVLTCPSEKEQQEWLESL 355
Cdd:cd01265    71 PGRVHILKASTRQAMLYWLQAL 92