Pleckstrin homology domain-containing family M member 1 Pleckstrin homology (PH) domain; PLEKHM1 is thought to function in vesicular transport in osteoclasts. Mutations in the PLEKHM1 gene are associated with osteopetrosis OPTB6. PLEKHM1 contains an N-terminal RUN domain (RPIP8/RaP2 interacting protein 8, UNC-14 and NESCA/new molecule containing SH3 at the carboxyl-terminus), followed by a PH domain, and either a C1 domain or a DUF4206 domain at its C-terminus. The RUN domain is thought to be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. 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 2462559250 448 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 527
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559250 528 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 578
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

RUN domain; RUN domain, named after RPIP8 (Rap2 interacting protein 8), UNC-14 and NESCA (new molecule containing SH3 at the carboxyl-terminus), is a less conserved protein motif that comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases. RUN domains are often found in proteins linked particularly to the functions of GTPases in the Rap and Rab families, suggesting the RUN domain may be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. RUN domain-containing proteins could hence play important roles in multiple Ras-like GTPase signalling pathways.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  48 RHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17679    82 RDVIDQIEHLSQITTDVGRCRAWIRLALNDGLLESYLEAILKDKSALKSYYNPSAFLRDPEQLDILKSLLQGLESFQFEL 161

                          90
                  ....*....|
gi 2462559250 128 SYKSAILNEW 137
Cdd:cd17679   162 PYNSSLLNTW 171

Pleckstrin homology domain-containing family M member 1 Pleckstrin homology (PH) domain; PLEKHM1 is thought to function in vesicular transport in osteoclasts. Mutations in the PLEKHM1 gene are associated with osteopetrosis OPTB6. PLEKHM1 contains an N-terminal RUN domain (RPIP8/RaP2 interacting protein 8, UNC-14 and NESCA/new molecule containing SH3 at the carboxyl-terminus), followed by a PH domain, and either a C1 domain or a DUF4206 domain at its C-terminus. The RUN domain is thought to be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. 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 2462559250 448 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 527
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559250 528 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 578
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

RUN domain found in pleckstrin homology domain-containing family M member 1 (PLEKHM1) and similar proteins; PLEKHM1, also called PH domain-containing family M member 1, or 162 kDa adapter protein (AP162), may act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. This model represents the RUN domain of PLEKHM1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  48 RHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17679    82 RDVIDQIEHLSQITTDVGRCRAWIRLALNDGLLESYLEAILKDKSALKSYYNPSAFLRDPEQLDILKSLLQGLESFQFEL 161

                          90
                  ....*....|
gi 2462559250 128 SYKSAILNEW 137
Cdd:cd17679   162 PYNSSLLNTW 171

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462559250   67 CRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYK 130
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEELLSKYYEPWAFLRDPEEGEQLLGLLVGLSALDFNLPVD 64

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 2462559250  634 IKESLLYLYMD---RTWMPYIFSLSLEALKCFRIRNNEK--------MLSDShgveTIRDILPDTSLGGPSFFKIITA-K 701
Cdd:smart00233   2 IKEGWLYKKSGggkKSWKKRYFVLFNSTLLYYKSKKDKKsykpkgsiDLSGC----TVREAPDPDSSKKPHCFEIKTSdR 77

                           90       100
                   ....*....|....*....|....*
gi 2462559250  702 AVLKLQAGNAEEAALWRDLVRKVLA 726
Cdd:smart00233  78 KTLLLQAESEEEREKWVEALRKAIA 102

Pleckstrin homology domain-containing family M member 1 Pleckstrin homology (PH) domain; PLEKHM1 is thought to function in vesicular transport in osteoclasts. Mutations in the PLEKHM1 gene are associated with osteopetrosis OPTB6. PLEKHM1 contains an N-terminal RUN domain (RPIP8/RaP2 interacting protein 8, UNC-14 and NESCA/new molecule containing SH3 at the carboxyl-terminus), followed by a PH domain, and either a C1 domain or a DUF4206 domain at its C-terminus. The RUN domain is thought to be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. 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 2462559250 448 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 527
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559250 528 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 578
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

RUN domain found in pleckstrin homology domain-containing family M member 1 (PLEKHM1) and similar proteins; PLEKHM1, also called PH domain-containing family M member 1, or 162 kDa adapter protein (AP162), may act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. This model represents the RUN domain of PLEKHM1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  48 RHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17679    82 RDVIDQIEHLSQITTDVGRCRAWIRLALNDGLLESYLEAILKDKSALKSYYNPSAFLRDPEQLDILKSLLQGLESFQFEL 161

                          90
                  ....*....|
gi 2462559250 128 SYKSAILNEW 137
Cdd:cd17679   162 PYNSSLLNTW 171

RUN domain; RUN domain, named after RPIP8 (Rap2 interacting protein 8), UNC-14 and NESCA (new molecule containing SH3 at the carboxyl-terminus), is a less conserved protein motif that comprises six conserved regions, which in some proteins have considerable insertions between them. The domain core is thought to take up a predominantly alpha fold, with basic amino acids in regions A and D possibly playing a functional role in interactions with Ras GTPases. RUN domains are often found in proteins linked particularly to the functions of GTPases in the Rap and Rab families, suggesting the RUN domain may be involved in Rab-mediated membrane trafficking, possibly as a Rab-binding site. RUN domain-containing proteins could hence play important roles in multiple Ras-like GTPase signalling pathways.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  41 WTPRLPSRHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGL 120
Cdd:cd17671    68 LLPAPSLKQAIRDINSLSNVKTDDGRGRAWIRLALNEKSLESYLAALLSDQSLLRKYYEPWALLRDPEEAELFLSLLVGL 147

                  ....*..
gi 2462559250 121 TSLSFEL 127
Cdd:cd17671   148 SSLDFNL 154

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462559250   67 CRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYK 130
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEELLSKYYEPWAFLRDPEEGEQLLGLLVGLSALDFNLPVD 64

RUN domain found in RUN and FYVE domain-containing proteins, RUFY1, RUFY2, RUFY3 and similar proteins; This family includes RUN and FYVE domain-containing protein RUFY1, RUFY2, and RUFY3. RUFY1, also called FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homolog of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY2, also called Rab4-interacting protein related, is a novel embryonic factor that is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. RUFY3, also called Rap2-interacting protein x (RIPx or RPIPx), or single axon-regulated protein (singar), is an N-terminal RUN domain and a C-terminal FYVE domain containing protein predominantly expressed in the brain. It suppresses formation of surplus axons for neuronal polarity. Unlike other RUFY proteins, RUFY3 can associate with the GTP-bound active form of Rab5. RUFY1, RUFY2, and RUFY3 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between; this model represents the RUN domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462559250  50 IISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDaEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17681    79 ITASVRDLPGIKTPLGRARAWLRLALMQKKLADYFRALIENKDLLSEFYEPGALMMS-EEAVVIAGLLVGLNVIDCNL 155

RUN1 domain found in DENN domain-containing protein 5 (DENND5) and similar proteins; DENND5 has been characterized as Rab6-interacting protein which is composed of an N-terminal DENN (Differentially Expressed in Normal and Neoplastic cells) domain followed by two RUN (RPIP8 [RaP2-interacting protein 8], UNC-14, and NESCA [new molecule containing SH3 at the carboxyl terminus]) domains flanking a PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain. It functions in membrane trafficking at a crossroads between the Golgi and the endosomal system. DENND5 has two isoforms, DENND5A and DENND5B. This model represents the first RUN domain of DENND5.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2462559250  48 RHIISELEhltfVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEfllSFLQGLTSL 123
Cdd:cd17677   102 KNVQNMKE----IKTDVGYARAWIRLALEKKLLSKHLKTLLSNQDLLRSLYKRYAFLRCEDERE---QFLYHLLSL 170

RUN domain found in RUN and FYVE domain-containing protein 1 (RUFY1) and similar proteins; RUFY1, also called FYVE-finger protein EIP1, or La-binding protein 1, or Rab4-interacting protein (Rabip4), or Zinc finger FYVE domain-containing protein 12 (ZFY12), a human homolog of mouse Rabip4, an effector of Rab4 GTPase that regulates recycling of endocytosed cargo. RUFY1 is an endosomal protein that functions as a dual effector of Rab4 and Rab14 and is involved in efficient recycling of transferrin (Tfn). It is a downstream effector of Etk, a downstream tyrosine kinase of PI3-kinase that is involved in regulation of vesicle trafficking. RUFY1 contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between; this model represents the RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  47 SRHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDaEEGEFLLSFLQGLTSLSFE 126
Cdd:cd17694    76 ASDIATSARNLPELKTAVGRGRAWLHLALMQKKLADYLKVLIDRKDLLSEFYEPGALMME-EEGAVIVGLLVGLNVIDAN 154

                  .
gi 2462559250 127 L 127
Cdd:cd17694   155 L 155

RUN domain found in RUN and FYVE domain-containing protein 4 (RUFY4), FYVE and coiled-coil domain-containing protein 1 (FYCO1), and similar proteins; The family includes RUFY4 and FYCO1. RUFY4 acts as a positive regulator that enhances autophagy and lysosome tethering in response to Interleukin-4. It is expressed in a cell-specific manner or under specific immunological conditions associated with IL4 expression such as allergic asthma. FYCO1, also called zinc finger FYVE domain-containing protein 7 (ZFYVE7), is a multidomain autophagy adaptor protein that interacts with kinesin motor proteins and with the autophagosomal membrane components microtubule-associated protein 1 light chain 3 (LC3), Rab7, and phosphatidylinositol 3-phosphate (PI3P), to mediate microtubule plus-end-directed autophagosome transport. Both RUFY4 and FYCO1 contain an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between; this model represents the RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462559250  28 LREWRCFQWW----RMDWTPRLPSRHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTAL 103
Cdd:cd17682    47 GRRKDYWDWLeellKKLNKIPKSLSDAVKFVKSCKKVKTNQGRGRLFIRYALNKKCLHDPVQQLVKNPKLLSDYYSPDSI 126

                          90       100
                  ....*....|....*....|....
gi 2462559250 104 LRDAEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17682   127 LGNEILSEILLSLLYQLNEINFDL 150

RUN domain found in RUN domain-containing protein 3 (RUNDC3) and similar proteins; RUNDC3 contains two isoforms, RUNDC3A and RUNDC3B. RUNDC3A, also called Rap2-interacting protein 8 (RPIP8), may act as an effector of Rap2A GTPase in neuronal cells. RUNDC3B, also called Rap2-binding protein 9, or Rap2-interacting protein 9 (RPIP-9), contains a RUN domain in its N-terminal region that mediates interaction with Rap2, an important component of the Mitogen-Activated Protein Kinase (MAPK) cascade, which regulates cellular proliferation and differentiation. It also contains characteristic binding sites for MAPK intermediates. Both RUNDC3A and RUNDC3B contain a RUN domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2462559250  51 ISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRdAEEGEFLLSFLQGLTSLSFEL 127
Cdd:cd17684    75 IASIEQMENIKSPKAKGRAWIRVALMEKRLSEYLSTALKQTRLTRNFYQDGAIML-SEDATVLCGMLIGLNAIDFSF 150

Pleckstrin homology (PH) domain; 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 2462559250 488 GTVERRGA--MGIWKELFCELSplEFRLYLSNEEH----TCVENCSLLRCESVGPAHSDGR---FELVFS-GKKLALRAS 557
Cdd:cd00821     3 GYLLKRGGggLKSWKKRWFVLF--EGVLLYYKSKKdssyKPKGSIPLSGILEVEEVSPKERphcFELVTPdGRTYYLQAD 80

                          90
                  ....*....|..
gi 2462559250 558 SQDEAEDWLDRV 569
Cdd:cd00821    81 SEEERQEWLKAL 92

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 2462559250  634 IKESLLYLYMD---RTWMPYIFSLSLEALKCFRIRNNEK--------MLSDShgveTIRDILPDTSLGGPSFFKIITA-K 701
Cdd:smart00233   2 IKEGWLYKKSGggkKSWKKRYFVLFNSTLLYYKSKKDKKsykpkgsiDLSGC----TVREAPDPDSSKKPHCFEIKTSdR 77

                           90       100
                   ....*....|....*....|....*
gi 2462559250  702 AVLKLQAGNAEEAALWRDLVRKVLA 726
Cdd:smart00233  78 KTLLLQAESEEEREKWVEALRKAIA 102

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 1; ARAP proteins (also called centaurin delta) are phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating proteins that modulate actin cytoskeleton remodeling by regulating ARF and RHO family members. They bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding. There are 3 mammalian ARAP proteins: ARAP1, ARAP2, and ARAP3. All ARAP proteins contain a N-terminal SAM (sterile alpha motif) domain, 5 PH domains, an ArfGAP domain, 2 ankyrin domain, A RhoGap domain, and a Ras-associating domain. This hierarchy contains the first PH domain in ARAP. 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 2462559250 484 LMKLGTverRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCSLlRCESVGPAHSDGRFELVFSGKKLALRASSQDEAE 563
Cdd:cd13253     6 LDKQGG---QGNNKGFQKRWVVFDGLSLRYFDSEKDAYSKRIIPL-SAISTVRAVGDNKFELVTTNRTFVFRAESDDERN 81

                          90
                  ....*....|....*..
gi 2462559250 564 DWLdrvrEALQKVRPQQ 580
Cdd:cd13253    82 LWC----STLQAAISEY 94