Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs; Widespread domain present in Gyp6 and Gyp7, thereby giving rise to the notion that it performs a GTP-activator activity on Rab-like GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   625 GVPREHRPRVWRWLvhLRVQHLHTPGC---YQELLSRGQAREHPAARQIELDLNRTFPNNKHFTCPTSSFPDKLRRVLLA 701
Cdd:smart00164   4 GVPPSLRGVVWKLL--LNAQPMDTSADkdlYSRLLKETAPDDKSIVHQIEKDLRRTFPEHSFFQDKEGPGQESLRRVLKA 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   702 FSWQNPTIGYCQGLNRLAAIALLVLEEEESAFWCLVAIVETIMPaDYYCNTLTASQVDQRVLQDLLSEKLPRLMAHLGQH 781
Cdd:smart00164  82 YALYNPEVGYCQGMNFLAAPLLLVMEDEEDAFWCLVKLMERYGP-NFYLPDMSGLQLDLLQLDRLVKEYDPDLYKHLKDL 160

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 389565509   782 HVDLSLVTFNWFLVVFADSLISNILLRVWDAFLYEGTKVVFRYALAIFKYNEKEIL 837
Cdd:smart00164 161 GITPSLYALRWFLTLFARELPLEIVLRIWDVLFAEGSDFLFRVALALLKLHRDVLL 216

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   276 LTISFAQKAKRQNNTFPFFSEGITRNRTAQEKVAALEQQVLMLTKELKSQKELVKILHKALEAAQQEKRASSAYLAAAed 355
Cdd:TIGR02168  815 LNEEAANLRERLESLERRIAATERRLEDLEEQIEELSEDIESLAAEIEELEELIEELESELEALLNERASLEEALALL-- 892

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   356 KDRLELVRHKVRqiaELGRRVEALEQERESLAHTASLREQQVQELQQHVqllmdknhakQQVICKLSEKVTQDFTHPPDQ 435
Cdd:TIGR02168  893 RSELEELSEELR---ELESKRSELRRELEELREKLAQLELRLEGLEVRI----------DNLQERLSEEYSLTLEEAEAL 959

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 389565509   436 SPLRPDAAN--RDFLSQ-QGKIEHLK----DDMEAYRTQN---CFLNSEIHQVTK 480
Cdd:TIGR02168  960 ENKIEDDEEeaRRRLKRlENKIKELGpvnlAAIEEYEELKeryDFLTAQKEDLTE 1014

Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs; Widespread domain present in Gyp6 and Gyp7, thereby giving rise to the notion that it performs a GTP-activator activity on Rab-like GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   625 GVPREHRPRVWRWLvhLRVQHLHTPGC---YQELLSRGQAREHPAARQIELDLNRTFPNNKHFTCPTSSFPDKLRRVLLA 701
Cdd:smart00164   4 GVPPSLRGVVWKLL--LNAQPMDTSADkdlYSRLLKETAPDDKSIVHQIEKDLRRTFPEHSFFQDKEGPGQESLRRVLKA 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   702 FSWQNPTIGYCQGLNRLAAIALLVLEEEESAFWCLVAIVETIMPaDYYCNTLTASQVDQRVLQDLLSEKLPRLMAHLGQH 781
Cdd:smart00164  82 YALYNPEVGYCQGMNFLAAPLLLVMEDEEDAFWCLVKLMERYGP-NFYLPDMSGLQLDLLQLDRLVKEYDPDLYKHLKDL 160

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 389565509   782 HVDLSLVTFNWFLVVFADSLISNILLRVWDAFLYEGTKVVFRYALAIFKYNEKEIL 837
Cdd:smart00164 161 GITPSLYALRWFLTLFARELPLEIVLRIWDVLFAEGSDFLFRVALALLKLHRDVLL 216

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 389565509  47 KLCGYLSKFGGKGP-IRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLSSAVFDCKADAEEGIFEIKTPSRVITLKAA 125
Cdd:cd01265    1 RLCGYLNKLETRGLgLKGWKRRWFVLDESKCQLYYYRSPQDATPLGSIDLSGAAFSYDPEAEPGQFEIHTPGRVHILKAS 80

                         90       100
                 ....*....|....*....|..
gi 389565509 126 TKQAMLYWLQQLQMKRWEFHNS 147
Cdd:cd01265   81 TRQAMLYWLQALQSKRREYCNS 102

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 389565509    48 LCGYLSKFGGKGpIRGWKSRWFFYDERkcQLYYSRT---AQDANPLDSIDLSSAVFDCKADAEEG----IFEIKTPSR-V 119
Cdd:smart00233   3 KEGWLYKKSGGG-KKSWKKRYFVLFNS--TLLYYKSkkdKKSYKPKGSIDLSGCTVREAPDPDSSkkphCFEIKTSDRkT 79

                           90       100
                   ....*....|....*....|
gi 389565509   120 ITLKAATKQAMLYWLQQLQM 139
Cdd:smart00233  80 LLLQAESEEEREKWVEALRK 99

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   276 LTISFAQKAKRQNNTFPFFSEGITRNRTAQEKVAALEQQVLMLTKELKSQKELVKILHKALEAAQQEKRASSAYLAAAed 355
Cdd:TIGR02168  815 LNEEAANLRERLESLERRIAATERRLEDLEEQIEELSEDIESLAAEIEELEELIEELESELEALLNERASLEEALALL-- 892

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   356 KDRLELVRHKVRqiaELGRRVEALEQERESLAHTASLREQQVQELQQHVqllmdknhakQQVICKLSEKVTQDFTHPPDQ 435
Cdd:TIGR02168  893 RSELEELSEELR---ELESKRSELRRELEELREKLAQLELRLEGLEVRI----------DNLQERLSEEYSLTLEEAEAL 959

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 389565509   436 SPLRPDAAN--RDFLSQ-QGKIEHLK----DDMEAYRTQN---CFLNSEIHQVTK 480
Cdd:TIGR02168  960 ENKIEDDEEeaRRRLKRlENKIKELGpvnlAAIEEYEELKeryDFLTAQKEDLTE 1014

Chromosome segregation ATPase Smc [Cell cycle control, cell division, chromosome partitioning];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509 302 RTAQEKVAALEQQVLMLTKEL-KSQKELVKILHKALEAAQQEKRASSAYLAAAEDKDRLEL-VRHKVRQIAELGRRVEAL 379
Cdd:COG1196  242 EELEAELEELEAELEELEAELaELEAELEELRLELEELELELEEAQAEEYELLAELARLEQdIARLEERRRELEERLEEL 321

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509 380 EQERESLAHTASLREQQVQELQQHVQLLMDKNHAKQQVICKLSEKVtqdfthppdqsplrpDAANRDFLSQQGKIEHLKD 459
Cdd:COG1196  322 EEELAELEEELEELEEELEELEEELEEAEEELEEAEAELAEAEEAL---------------LEAEAELAEAEEELEELAE 386

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509 460 DMEAYRTQNCFLNSEIHQVTKIWRKVAEKEKALLTKCAYLQARNCQVESKYLAGLRRLQEALGDEASECSEL--LRQLVQ 537
Cdd:COG1196  387 ELLEALRAAAELAAQLEELEEAEEALLERLERLEEELEELEEALAELEEEEEEEEEALEEAAEEEAELEEEEeaLLELLA 466

                        250       260
                 ....*....|....*....|..
gi 389565509 538 EALQWEAGEASSDSIELSPISK 559
Cdd:COG1196  467 ELLEEAALLEAALAELLEELAE 488

phosphodiesterase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509 300 RNRTAQEKVAALEQQ-VLML---TKELKSQKELVKI-----LHKALEAAQQEKRASSAYLAAAEDK--DRLELVRHKVRQ 368
Cdd:PRK12704  25 RKKIAEAKIKEAEEEaKRILeeaKKEAEAIKKEALLeakeeIHKLRNEFEKELRERRNELQKLEKRllQKEENLDRKLEL 104

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 389565509 369 IAELGRRVEALEQERESLAHTASLREQQVQEL-QQHVQLL-----MDKNHAKQQVICKLSEKVTQD 428
Cdd:PRK12704 105 LEKREEELEKKEKELEQKQQELEKKEEELEELiEEQLQELerisgLTAEEAKEILLEKVEEEARHE 170

Domain in Tre-2, BUB2p, and Cdc16p. Probable Rab-GAPs; Widespread domain present in Gyp6 and Gyp7, thereby giving rise to the notion that it performs a GTP-activator activity on Rab-like GTPases.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   625 GVPREHRPRVWRWLvhLRVQHLHTPGC---YQELLSRGQAREHPAARQIELDLNRTFPNNKHFTCPTSSFPDKLRRVLLA 701
Cdd:smart00164   4 GVPPSLRGVVWKLL--LNAQPMDTSADkdlYSRLLKETAPDDKSIVHQIEKDLRRTFPEHSFFQDKEGPGQESLRRVLKA 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   702 FSWQNPTIGYCQGLNRLAAIALLVLEEEESAFWCLVAIVETIMPaDYYCNTLTASQVDQRVLQDLLSEKLPRLMAHLGQH 781
Cdd:smart00164  82 YALYNPEVGYCQGMNFLAAPLLLVMEDEEDAFWCLVKLMERYGP-NFYLPDMSGLQLDLLQLDRLVKEYDPDLYKHLKDL 160

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 389565509   782 HVDLSLVTFNWFLVVFADSLISNILLRVWDAFLYEGTKVVFRYALAIFKYNEKEIL 837
Cdd:smart00164 161 GITPSLYALRWFLTLFARELPLEIVLRIWDVLFAEGSDFLFRVALALLKLHRDVLL 216

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 389565509  47 KLCGYLSKFGGKGP-IRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLSSAVFDCKADAEEGIFEIKTPSRVITLKAA 125
Cdd:cd01265    1 RLCGYLNKLETRGLgLKGWKRRWFVLDESKCQLYYYRSPQDATPLGSIDLSGAAFSYDPEAEPGQFEIHTPGRVHILKAS 80

                         90       100
                 ....*....|....*....|..
gi 389565509 126 TKQAMLYWLQQLQMKRWEFHNS 147
Cdd:cd01265   81 TRQAMLYWLQALQSKRREYCNS 102

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 389565509  48 LCGYLSKFGGKGpIRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLSS--AVFDCKADAEEGIFEIKTP-SRVITLKA 124
Cdd:cd00821    1 KEGYLLKRGGGG-LKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGilEVEEVSPKERPHCFELVTPdGRTYYLQA 79

                         90
                 ....*....|...
gi 389565509 125 ATKQAMLYWLQQL 137
Cdd:cd00821   80 DSEEERQEWLKAL 92

Set binding factor 1 (also called Human MTMR5) Pleckstrin Homology (PH) domain; Sbf1 is a myotubularin-related pseudo-phosphatase. Both Sbf1 and myotubularin interact with the SET domains of Hrx and other epigenetic regulatory proteins, but Sbf1 lacks phosphatase activity due to several amino acid changes in its structurally preserved catalytic pocket. It contains pleckstrin (PH), GEF, and myotubularin homology domains that are thought to be responsible for signaling and growth control. Sbf1 functions as an inhibitor of cellular growth. The N-terminal GEF homology domain serves to inhibit the transforming effects of Sbf1. 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 389565509  50 GYLSKFGGKgpIRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLS--SAVFDC-------KADAEEGIFEIKTPSRVI 120
Cdd:cd01235    7 GYLYKRGAL--LKGWKQRWFVLDSTKHQLRYYESREDTKCKGFIDLAevESVTPAtpiigapKRADEGAFFDLKTNKRVY 84

                         90       100
                 ....*....|....*....|.
gi 389565509 121 TL---KAATKQAMLYWLQQLQ 138
Cdd:cd01235   85 NFcafDAESAQQWIEKIQSCL 105

Myosin X Pleckstrin homology (PH) domain, repeat 2; MyoX, a MyTH-FERM myosin, is a molecular motor that has crucial functions in the transport and/or tethering of integrins in the actin-based extensions known as filopodia, microtubule binding, and in netrin-mediated axon guidance. It functions as a dimer. MyoX walks on bundles of actin, rather than single filaments, unlike the other unconventional myosins. MyoX is present in organisms ranging from humans to choanoflagellates, but not in Drosophila and Caenorhabditis elegans.MyoX consists of a N-terminal motor/head region, a neck made of 3 IQ motifs, and a tail consisting of a coiled-coil domain, a PEST region, 3 PH domains, a myosin tail homology 4 (MyTH4), and a FERM domain at its very C-terminus. The first PH domain in the MyoX tail is a split-PH domain, interupted by the second PH domain such that PH 1a and PH 1b flanks PH 2. The third PH domain (PH 3) follows the PH 1b domain. This cd contains the second PH 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 389565509  49 CGYLSKFGGKGPI---RGWKSRWFfyDERKCQLYYSRTAQD-ANPLDSIDLSSAVFDCKADAEEGIFEIKTPSRVITLKA 124
Cdd:cd13296    2 SGWLTKKGGGSSTlsrRNWKSRWF--VLRDTVLKYYENDQEgEKLLGTIDIRSAKEIVDNDPKENRLSITTEERTYHLVA 79

                         90
                 ....*....|...
gi 389565509 125 ATKQAMLYWLQQL 137
Cdd:cd13296   80 ESPEDASQWVNVL 92

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 389565509  50 GYLSKFGGKgpIRGWKSRWFFYdeRKCQLYYSRTAQDAN--PLDSIDLSSAvfdCK-ADAEEG-IFEIKTPSRVITLKAA 125
Cdd:cd13282    3 GYLTKLGGK--VKTWKRRWFVL--KNGELFYYKSPNDVIrkPQGQIALDGS---CEiARAEGAqTFEIVTEKRTYYLTAD 75

                         90
                 ....*....|...
gi 389565509 126 TKQAMLYWLQQLQ 138
Cdd:cd13282   76 SENDLDEWIRVIQ 88

General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 and the related proteins ARNO (ARF nucleotide-binding site opener)/cytohesin-2 and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. The PH domains of all three proteins exhibit relatively high affinity for PtdIns(3,4,5)P3. Within the Grp1 family, diglycine (2G) and triglycine (3G) splice variants, differing only in the number of glycine residues in the PH domain, strongly influence the affinity and specificity for phosphoinositides. The 2G variants selectively bind PtdIns(3,4,5)P3 with high affinity,the 3G variants bind PtdIns(3,4,5)P3 with about 30-fold lower affinity and require the polybasic region for plasma membrane targeting. These ARF-GEFs share a common, tripartite structure consisting of an N-terminal coiled-coil domain, a central domain with homology to the yeast protein Sec7, a PH domain, and a C-terminal polybasic region. The Sec7 domain is autoinhibited by conserved elements proximal to the PH domain. GRP1 binds to the DNA binding domain of certain nuclear receptors (TRalpha, TRbeta, AR, ER, but not RXR), and can repress thyroid hormone receptor (TR)-mediated transactivation by decreasing TR-complex formation on thyroid hormone response elements. ARNO promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion. Cytohesin acts as a PI 3-kinase effector mediating biological responses including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 389565509  50 GYLSKFGGKgpIRGWKSRWFFYDErKCqLYYSRTAQDANPLDSIDLSS-AVFDCKADAEEGIFEIKTPSRVITLKAA 125
Cdd:cd01252    7 GWLLKLGGR--VKSWKRRWFILTD-NC-LYYFEYTTDKEPRGIIPLENlSVREVEDKKKPFCFELYSPSNGQVIKAC 79

Fungal proteins Pleckstrin homology (PH) domain, repeat 1; The functions of these fungal proteins are unknown, but they all contain 2 PH domains. This cd represents the first PH 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 389565509  50 GYLSKFGGKgpIRGWKSRWFFYdeRKCQLYYSRTAQDANPLDSIDLS--SAVFDCKADAEEGIFEIKTPSRVITLKAATK 127
Cdd:cd13298   10 GYLLKRSRK--TKNWKKRWVVL--RPCQLSYYKDEKEYKLRRVINLSelLAVAPLKDKKRKNVFGIYTPSKNLHFRATSE 85

                         90
                 ....*....|
gi 389565509 128 QAMLYWLQQL 137
Cdd:cd13298   86 KDANEWVEAL 95

Domain of unknown function (DUF4686); This family of proteins is found in eukaryotes. Proteins in this family are typically between 498 and 775 amino acids in length. There is a conserved DLK sequence motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509  305 QEKVAALEQQVLMLTKELKSQKELVKIL-----------HKALEAAQQEKRASSAYL--AAAEDKDRLElvrhkvRQIAE 371
Cdd:pfam15742  89 QQKIRELELEVLKQAQSIKSQNSLQEKLaqeksrvadaeEKILELQQKLEHAHKVCLtdTCILEKKQLE------ERIKE 162

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 389565509  372 LGRRVEALEQERESLAHTASLREQQVQELQQHVQLLMDKNHAKQQVICKLSEKVTQ 427
Cdd:pfam15742 163 ASENEAKLKQQYQEEQQKRKLLDQNVNELQQQVRSLQDKEAQLEMTNSQQQLRIQQ 218

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. 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 389565509  50 GYLSKFGGKGPiRGWKSRWFFYDERkcQLYYSRTAQDanpldsiDLSSAVFD----CKADAEEGI-----FEIKTPSRVI 120
Cdd:cd13250    3 GYLFKRSSNAF-KTWKRRWFSLQNG--QLYYQKRDKK-------DEPTVMVEdlrlCTVKPTEDSdrrfcFEVISPTKSY 72

                         90
                 ....*....|....*...
gi 389565509 121 TLKAATKQAMLYWLQQLQ 138
Cdd:cd13250   73 MLQAESEEDRQAWIQAIQ 90

Phosphoinositol 3-phosphate binding proteins 1, 2, and 3 pleckstrin homology (PH) domain; PEPP1 (also called PLEKHA4/PH domain-containing family A member 4 and RHOXF1/Rhox homeobox family member 1), and related homologs PEPP2 (also called PLEKHA5/PH domain-containing family A member 5) and PEPP3 (also called PLEKHA6/PH domain-containing family A member 6), have PH domains that interact specifically with PtdIns(3,4)P3. Other proteins that bind PtdIns(3,4)P3 specifically are: TAPP1 (tandem PH-domain-containing protein-1) and TAPP2], PtdIns3P AtPH1, and Ptd- Ins(3,5)P2 (centaurin-beta2). All of these proteins contain at least 5 of the 6 conserved amino acids that make up the putative phosphatidylinositol 3,4,5- trisphosphate-binding motif (PPBM) located at their N-terminus. 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 389565509  50 GYLSKFGGKGPiRGWKSRWFFYdeRKCQLYYSRTAQDANPLDSIDLSS-AVFDCKADAEEgifeiktpSRVITLKAATKQ 128
Cdd:cd13248   11 GWLHKQGGSGL-KNWRKRWFVL--KDNCLYYYKDPEEEKALGSILLPSyTISPAPPSDEI--------SRKFAFKAEHAN 79

                         90
                 ....*....|....*..
gi 389565509 129 AMLYWL---QQLQMKRW 142
Cdd:cd13248   80 MRTYYFaadTAEEMEQW 96

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 389565509  50 GYLSKFGGKgPIRGWKSRWFFYDERKcqLYYSRTAQDANPLDSIDLSSAV--FDCKADAEEGI-------FEIKTPSRVI 120
Cdd:cd01251    6 GYLEKTGPK-QTDGFRKRWFTLDDRR--LMYFKDPLDAFPKGEIFIGSKEegYSVREGLPPGIkghwgfgFTLVTPDRTF 82

                         90
                 ....*....|....*...
gi 389565509 121 TLKAATKQAMLYWLQQLQ 138
Cdd:cd01251   83 LLSAETEEERREWITAIQ 100

Pleckstrin homology domain; This Pleckstrin homology domain is found in some fungal species.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 389565509   49 CGYLSKFGGKGpirgWKSRWF---------FY-DERKCQLYYSRTAQDA--NPLDSIDLSSAVFDCKADA----EEGIFE 112
Cdd:pfam15413   2 EGYLKKKGPKT----WKHRWFavlrngvlfYYkSEKMKVVKHVIVLSNYivGKLGTDIISGALFKIDNIRsetsDDLLLE 77

                          90       100
                  ....*....|....*....|....*.
gi 389565509  113 IKTPSRVITLKAATKQAMLYWLQQLQ 138
Cdd:pfam15413  78 ISTETKIFFLYGDNNEETYEWVEALQ 103

Sesquipedalian family Pleckstrin homology (PH) domain; The sesquipedalian family has 2 mammalian members: Ses1 and Ses2, which are also callled 7 kDa inositol polyphosphate phosphatase-interacting protein 1 and 2. They play a role in endocytic trafficking and are required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane. Members of this family form homodimers and heterodimers. Sesquipedalian interacts with inositol polyphosphate 5-phosphatase OCRL-1 (INPP5F) also known as Lowe oculocerebrorenal syndrome protein, a phosphatase enzyme that is involved in actin polymerization and is found in the trans-Golgi network and INPP5B. Sesquipedalian contains a single 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 389565509  50 GYLSKFGGKGpiRGWKSRWF-------FYDERKcqlyysrtaQDANPLDSIDLSSAVFDCKADAEEGIFEIKTP---SRV 119
Cdd:cd13288   12 GYLWKKGERN--TSYQKRWFvlkgnllFYFEKK---------GDREPLGVIVLEGCTVELAEDAEPYAFAIRFDgpgARS 80

                         90       100
                 ....*....|....*....|....*
gi 389565509 120 ITLKAATKQAMLYWLQQLQMKRWEF 144
Cdd:cd13288   81 YVLAAENQEDMESWMKALSRASYDY 105

Pleckstrin 2 Pleckstrin homology (PH) domain, repeat 2; Pleckstrin is a protein found in platelets. This name is derived from platelet and leukocyte C kinase substrate and the KSTR string of amino acids. Pleckstrin 2 contains two PH domains and a DEP (dishvelled, egl-10, and pleckstrin) domain. Unlike pleckstrin 1, pleckstrin 2 does not contain obvious sites of PKC phosphorylation. Pleckstrin 2 plays a role in actin rearrangement, large lamellipodia and peripheral ruffle formation, and may help orchestrate cytoskeletal arrangement. The PH domains of pleckstrin 2 are thought to contribute to lamellipodia formation. 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 389565509  50 GYLSKFGGKgpIRGWKSRWFFYDERKCQLYYSRTAQDANPLDSIDLS----SAVFD----CKADAEEGIFEIKTPSRV-I 120
Cdd:cd13302   11 GCLLKQGHR--RKNWKVRKFVLRDDPAYLHYYDPAKGEDPLGAIHLRgcvvTAVEDnsnpRKGSVEGNLFEIITADEVhY 88

                         90
                 ....*....|....*....
gi 389565509 121 TLKAATKQAMLYWLQQLQM 139
Cdd:cd13302   89 YLQAATPAERTEWIKAIQM 107

Pleckstrin homology-like domain-containing family B member 2 pleckstrin homology (PH) domain; PHLDB2 (also called LL5beta) and PHLDB1 (also called LL5alpha) are cytoskeleton- and membrane-associated proteins. PHLDB2 has been identified as a key component of the synaptic podosomes that play an important role in in postsynaptic maturation. Both are large proteins containing an N-terminal pleckstrin (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 389565509  47 KLC-GYLSKFGGKgpIRGWKSRWFFYDERKCQLYYsRTAQDANPLDSIDLSSAV----FDCKADAEEG-----IFEIKTP 116
Cdd:cd14673    3 KRCrGFLTKMGGK--IKTWKKRWFVFDRNKRTLSY-YVDKHEKKLKGVIYFQAIeevyYDHLRSAAKSpnpalTFCVKTH 79

                         90
                 ....*....|....*...
gi 389565509 117 SRVITLKAATKQAMLYWL 134
Cdd:cd14673   80 DRLYYMVAPSPEAMRIWM 97