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 2462559254 369 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 448
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559254 449 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 499
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 2462559254  555 IKESLLYLYMD---RTWMPYIFSLSLEALKCFRIRNNEK--------MLSDShgveTIRDILPDTSLGGPSFFKIITA-K 622
Cdd:smart00233   2 IKEGWLYKKSGggkKSWKKRYFVLFNSTLLYYKSKKDKKsykpkgsiDLSGC----TVREAPDPDSSKKPHCFEIKTSdR 77

                           90       100
                   ....*....|....*....|....*
gi 2462559254  623 AVLKLQAGNAEEAALWRDLVRKVLA 647
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 2462559254 369 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 448
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559254 449 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 499
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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2462559254   1 MECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYKS 52
Cdd:pfam02759  83 LDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains); Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 2462559254  857 HVYHCDLCTQRGFiCQICQHHDIIFpfeFDTTVRCAECKTVFHQSCQAVVKKGC 910
Cdd:smart00109   1 HKHVFRTFTKPTF-CCVCRKSIWGS---FKQGLRCSECKVKCHKKCADKVPKAC 50

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 2462559254  555 IKESLLYLYMD---RTWMPYIFSLSLEALKCFRIRNNEK--------MLSDShgveTIRDILPDTSLGGPSFFKIITA-K 622
Cdd:smart00233   2 IKEGWLYKKSGggkKSWKKRYFVLFNSTLLYYKSKKDKKsykpkgsiDLSGC----TVREAPDPDSSKKPHCFEIKTSdR 77

                           90       100
                   ....*....|....*....|....*
gi 2462559254  623 AVLKLQAGNAEEAALWRDLVRKVLA 647
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 2462559254 369 VPSPGRRqaqAAPSQGHKSFRVVHRRQMGLSNPFRGLMKLGTVERRGAMGIWKELFCELSPLEFRLYLSNEEHTCVENCS 448
Cdd:cd13321     5 APSQGPL---SEPSQVQKPFSVVHRRQMGLSNPFRGLLKLGTLERRGAMGIWKEFYCELSPLEFRLYLSAEERVCVENCS 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462559254 449 LLRCESVGPAHSDGRFELVFSGKKLALRASSQDEAEDWLDRVREALQKVRP 499
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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2462559254   1 MECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELSYKS 52
Cdd:pfam02759  83 LDQWLKLLLSNKELLSEYYEPWALLADPEFGEILLGLLVGLSALDFNLCLKL 134

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
                  ....*....|....*....|....*....|....*....|....*...
gi 2462559254   1 MECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 48
Cdd:cd17671   107 LESYLAALLSDQSLLRKYYEPWALLRDPEEAELFLSLLVGLSSLDFNL 154

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
                  ....*....|....*....|....*....|....*....|....*....
gi 2462559254   1 MECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFELS 49
Cdd:cd17689   116 LERYLHILLSNENLLRQYYEDWAFLRDEERSSMLPNMAAGLGSILFALS 164

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 2462559254 409 GTVERRGA--MGIWKELFCELSplEFRLYLSNEEH----TCVENCSLLRCESVGPAHSDGR---FELVFS-GKKLALRAS 478
Cdd:cd00821     3 GYLLKRGGggLKSWKKRWFVLF--EGVLLYYKSKKdssyKPKGSIPLSGILEVEEVSPKERphcFELVTPdGRTYYLQAD 80

                          90
                  ....*....|..
gi 2462559254 479 SQDEAEDWLDRV 490
Cdd:cd00821    81 SEEERQEWLKAL 92

RUN domain found in pleckstrin homology domain-containing family M member 2 (PLEKHM2) and similar proteins; PLEKHM2, also called PH domain-containing family M member 2, or Salmonella-induced filaments A (SifA) and Kinesin-Interacting Protein (SKIP), is the lysosome, melanosome and lytic granule cargo adaptor that controls lysosome positioning using a composite kinesin-1 heavy and light chain-binding domain. In addition to kinesin-1, it also interacts with several Rabs to affect endosomal trafficking. This model represents the RUN domain of PLEKHM2.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2462559254   1 MECYLKLLLQEQARLHEYYQPTALLRDAEEGEFLLSFLQGLTSLSFEL 48
Cdd:cd17680    98 LESYLRSFLENRKLVKKFYHKHALLRDSQRLELLLTLLSGLEFVQFDL 145