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 2462492997 499 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 578
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462492997 579 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 629
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

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 2462492997  685 IKESLLYLYMD---RTWMPYIFSLSLEALKCFRIRNNEK--------MLSDShgveTIRDILPDTSLGGPSFFKIITA-K 752
Cdd:smart00233   2 IKEGWLYKKSGggkKSWKKRYFVLFNSTLLYYKSKKDKKsykpkgsiDLSGC----TVREAPDPDSSKKPHCFEIKTSdR 77

                           90       100
                   ....*....|....*....|....*
gi 2462492997  753 AVLKLQAGNAEEAALWRDLVRKVLA 777
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 2462492997 499 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 578
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462492997 579 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 629
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

RUN domain; This domain is present in several proteins that are linked to the functions of GTPases in the Rap and Rab families. They could hence play important roles in multiple Ras-like GTPase signalling pathways. The domain is 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  49 TMCSALEAVFIHGLHAKHIRAEAGGKRKksahqkplPQPVFWPLLKAVT-----HKHIISELEHLTFVNT---DVGRCRA 120
Cdd:pfam02759   1 QLCAALEALLSHGLKRSSLLILRAAGLL--------PERSFWALLERVGklvppAEELLSSVQELEQIHTpysPDGRGRA 72

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2462492997 121 WLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYKS 182
Cdd:pfam02759  73 WIRLALNEKLLDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

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 2462492997  535 LMKLGTVERRGAMGI--WKELFCELSPLEFRLYLSNEEHTC--------VENCSLLRCESVGPAHSDGRFELVFS-GKKL 603
Cdd:smart00233   1 VIKEGWLYKKSGGGKksWKKRYFVLFNSTLLYYKSKKDKKSykpkgsidLSGCTVREAPDPDSSKKPHCFEIKTSdRKTL 80

                           90       100
                   ....*....|....*....|..
gi 2462492997  604 ALRASSQDEAEDWLDRVREALQ 625
Cdd:smart00233  81 LLQAESEEEREKWVEALRKAIA 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 2462492997 499 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 578
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462492997 579 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 629
Cdd:cd13321    82 LLRCESVGPAHSDGRFELVFPGKKLALRAPSRDEAEDWLDRIREALQKVRP 132

RUN domain; This domain is present in several proteins that are linked to the functions of GTPases in the Rap and Rab families. They could hence play important roles in multiple Ras-like GTPase signalling pathways. The domain is 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  49 TMCSALEAVFIHGLHAKHIRAEAGGKRKksahqkplPQPVFWPLLKAVT-----HKHIISELEHLTFVNT---DVGRCRA 120
Cdd:pfam02759   1 QLCAALEALLSHGLKRSSLLILRAAGLL--------PERSFWALLERVGklvppAEELLSSVQELEQIHTpysPDGRGRA 72

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2462492997 121 WLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYKS 182
Cdd:pfam02759  73 WIRLALNEKLLDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

RUN domain found in sorting nexin-29 (SNX29) and similar proteins; SNX29, also called RUN domain-containing protein 2A (RUNDC2A), belongs to the sorting nexin family. Sorting nexins are a large group of proteins that are localized in the cytoplasm and have the potential for membrane association either through their lipid-binding PX domain, a phospholipid-binding motif, or through protein-protein interactions with membrane-associated protein complexes. Some sorting nexin family members have been shown to facilitate protein sorting. This model contains the RUN domain of SNX29.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  21 KLVGSVKALQKQYVSLDTVVTSEDGDANTMCSALEAVFIHGL-----HAKHIRAEAGGKRKKSAHQKPLPQPVFWPLLKA 95
Cdd:cd17689     1 RLLDAVKQCQIRFGGKTELATESDSRVSCLCAQLEAVLQHGLktsrsPNLVSSAVTQVSGLAGSLGSAETEPTFWPFVKE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  96 VTHKHIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLS 175
Cdd:cd17689    81 HLTKHELERFELLKNIWTDIGRGRAWLRSALNEHSLERYLHILLSNENLLRQYYEDWAFLRDEERSSMLPNMAAGLGSIL 160

                  ....
gi 2462492997 176 FELS 179
Cdd:cd17689   161 FALS 164

domain involved in Ras-like GTPase signaling;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2462492997  118 CRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYK 181
Cdd:smart00593   1 FRAWIRLALNEKLLSSWLNLLLSDEELLSKYYEPWAFLRDPEEGEQLLGLLVGLSALDFNLPVD 64

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  50 MCSALEAVFIHGLHAK--------HIRAEAGGKRKksahQKPLPQPVFWPLlkavthKHIISELEhltfVNTDVGRCRAW 121
Cdd:cd17677    55 LCDLLERIWSHGLQTKqgksalwsHLLAYQENEER----LKPLPESLLFDM------KNVQNMKE----IKTDVGYARAW 120

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462492997 122 LRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEfllSFLQGLTSL 174
Cdd:cd17677   121 IRLALEKKLLSKHLKTLLSNQDLLRSLYKRYAFLRCEDERE---QFLYHLLSL 170

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 2462492997  50 MCSALEAVFIHGLHAKHIraeaGGKRKKSahqkplpqpvFWPLLKAVTHK---------HIISELEHLTFVNTDVGRCRA 120
Cdd:cd17682    27 FCETLEKILRKGLKEKVS----LGGRRKD----------YWDWLEELLKKlnkipkslsDAVKFVKSCKKVKTNQGRGRL 92

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2462492997 121 WLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 178
Cdd:cd17682    93 FIRYALNKKCLHDPVQQLVKNPKLLSDYYSPDSILGNEILSEILLSLLYQLNEINFDL 150

RUN1 domain found in DENN domain-containing protein 5A (DENND5A) and similar proteins; DENND5A, also called Rab6-interacting protein 1 (Rab6IP1), is present predominantly in developing neuronal tissue, and functions in membrane trafficking at a crossroads between the Golgi and the endosomal system. It 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. This model represents the first RUN domain of DENND5A.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  49 TMCSALEAVFIHGLHAK--------HIRAEAGGKRKK--------------SAHQKPLPQPVFWPLLKAVTH--KHIise 104
Cdd:cd17690    54 SLCDLLERIWSHGLQVKqgksalwsHLLHYQENRERKttssglstsgiildSERRKSDASLAMPPLKISLIQdmRHI--- 130

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2462492997 105 lEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLR-DAEEGEF---LLSF 167
Cdd:cd17690   131 -QNIGEIKTDVGKARAWVRLSMEKKLLSRHLKQLLSDHELTKKLYKRYAFLRcDDEKEQFlyhLLSF 196

RUN domain found in RUN and FYVE domain-containing protein 2 (RUFY2) and similar proteins; RUFY2, also called Rab4-interacting protein related, is a novel embryonic factor that contains an N-terminal RUN domain and a C-terminal FYVE domain with two coiled-coil domains in-between. It is present in the nucleus at early stages of embryonic development. It may have both endosomal functions in the cytoplasm and nuclear functions. This model represents the RUN domain of RUFY2.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2462492997 101 IISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRDaEEGEFLLSFLQGLTSLSFEL 178
Cdd:cd17695    79 IAASVRDLPGLKTPLGRARAWLRLALMQKKLADYLRCLIIRRDLLSEFYEYHALMME-EEGAVIVGLLVGLNVIDANL 155

RUN domain found in RUN domain-containing protein 3A (RUNDC3A) and similar proteins; RUN domain-containing protein 3A (RUNDC3A), also called Rap2-interacting protein 8 (RPIP8), may act as an effector of Rap2A GTPase in neuronal cells. It contains a RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  86 QPVFWPLLKAVTHK---HIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTA-LLRdaEEG 161
Cdd:cd17699    56 QRGFWDYIRLACSKvpnNCISSIENMENISTSRAKGRAWIRVALMEKRLSEYIATALRDTRTTRRFYDDGAiMLR--EES 133

                          90
                  ....*....|....*
gi 2462492997 162 EFLLSFLQGLTSLSF 176
Cdd:cd17699   134 TVLTGMLIGLSAIDF 148

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 2462492997 539 GTVERRGA--MGIWKELFCELSplEFRLYLSNEEH----TCVENCSLLRCESVGPAHSDGR---FELVFS-GKKLALRAS 608
Cdd:cd00821     3 GYLLKRGGggLKSWKKRWFVLF--EGVLLYYKSKKdssyKPKGSIPLSGILEVEEVSPKERphcFELVTPdGRTYYLQAD 80

                          90
                  ....*....|..
gi 2462492997 609 SQDEAEDWLDRV 620
Cdd:cd00821    81 SEEERQEWLKAL 92

RUN domain found in RUN domain-containing protein 3B (RUNDC3B) and similar proteins; RUN domain-containing protein 3B (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. RUNDC3B contains a RUN domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462492997  89 FWPLLKAVTHK---HIISELEHLTFVNTDVGRCRAWLRLALNDGLMECYLKLLLQEQARLHEYYQPTALLRdAEEGEFLL 165
Cdd:cd17700    59 FWDYIRVACSKvphNCICSIENMENVSSSRAKGRAWIRVALMEKRLSEYISTALRDFKTTRRFYEDGAIVL-GEEANMLA 137

                          90
                  ....*....|.
gi 2462492997 166 SFLQGLTSLSF 176
Cdd:cd17700   138 GMLLGLNAIDF 148