Engulfment and cell motility protein 1 pleckstrin homology (PH) domain; DOCK2 (Dedicator of cytokinesis 2), a hematopoietic cell-specific, atypical GEF, controls lymphocyte migration through Rac activation. A DOCK2-ELMO1 complex s necessary for DOCK2-mediated Rac signaling. DOCK2 contains a SH3 domain at its N-terminus, followed by a lipid binding DHR1 domain, and a Rac-binding DHR2 domain at its C-terminus. ELMO1, a mammalian homolog of C. elegans CED-12, contains the N-terminal RhoG-binding region, the ELMO domain, the PH domain, and the C-terminal sequence with three PxxP motifs. The C-terminal region of ELMO1, including the Pro-rich sequence, binds the SH3-containing region of DOCK2 forming a intermolecular five-helix bundle along with the PH domain of ELMO1. Autoinhibition of ELMO1 and DOCK2 is accomplished by the interactions of the EID and EAD domains and SH3 and DHR2 domains, respectively. The interaction of DOCK2 and ELMO1 mutually relieve their autoinhibition and results in the activation of Rac1. The PH domain of ELMO1 does not bind phosphoinositides due to the absence of key binding residues. It more closely resembles the FERM domain rather than other PH domains. 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 56118506 539 ELIKQQRLNRLCEGSSFRKTGNRRRQERFWFCRLALNHKVLHYGDLEDNVQGEvPYESLQEKIPVSDIKAVVTGKDCPHM 618
Cdd:cd13359   1 ELIKQQRLNFLVEGTLFPKYNARGRKDKFWYCRLSPNHKVLHYGDCEESAQPA-PLEELPEKLPVADIKALVTGKDCPHM 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 56118506 619 KEKSAlkqNKEVLELAFSILYDPDETLNFIAPNKYEYCIWIDGVNALLGR 668
Cdd:cd13359  80 KELKK---NKSVASLAFSILYDSDESLDFVAPNETVFDIWTDGLNALLGK 126

Engulfment and cell motility protein 1 pleckstrin homology (PH) domain; DOCK2 (Dedicator of cytokinesis 2), a hematopoietic cell-specific, atypical GEF, controls lymphocyte migration through Rac activation. A DOCK2-ELMO1 complex s necessary for DOCK2-mediated Rac signaling. DOCK2 contains a SH3 domain at its N-terminus, followed by a lipid binding DHR1 domain, and a Rac-binding DHR2 domain at its C-terminus. ELMO1, a mammalian homolog of C. elegans CED-12, contains the N-terminal RhoG-binding region, the ELMO domain, the PH domain, and the C-terminal sequence with three PxxP motifs. The C-terminal region of ELMO1, including the Pro-rich sequence, binds the SH3-containing region of DOCK2 forming a intermolecular five-helix bundle along with the PH domain of ELMO1. Autoinhibition of ELMO1 and DOCK2 is accomplished by the interactions of the EID and EAD domains and SH3 and DHR2 domains, respectively. The interaction of DOCK2 and ELMO1 mutually relieve their autoinhibition and results in the activation of Rac1. The PH domain of ELMO1 does not bind phosphoinositides due to the absence of key binding residues. It more closely resembles the FERM domain rather than other PH domains. 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 56118506 539 ELIKQQRLNRLCEGSSFRKTGNRRRQERFWFCRLALNHKVLHYGDLEDNVQGEvPYESLQEKIPVSDIKAVVTGKDCPHM 618
Cdd:cd13359   1 ELIKQQRLNFLVEGTLFPKYNARGRKDKFWYCRLSPNHKVLHYGDCEESAQPA-PLEELPEKLPVADIKALVTGKDCPHM 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 56118506 619 KEKSAlkqNKEVLELAFSILYDPDETLNFIAPNKYEYCIWIDGVNALLGR 668
Cdd:cd13359  80 KELKK---NKSVASLAFSILYDSDESLDFVAPNETVFDIWTDGLNALLGK 126

Pleckstrin homology domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56118506   541 IKQQRLNRLCEGSSFRKTGNRRRQERFWFCRLALNHKVLHYGDLEDNVQGEVPYESLQEKIPVSDIKAVVTGKDCPHMKE 620
Cdd:pfam16457   1 VKEQRLNCLLEGAWFPKVRGRRRKKKYRFCRLSPNRKVLHYGDFEEKPTVDPSLESLPEKIDLSDIKEVVTGKECPHVRE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 56118506   621 KSaLKQNKEVLELAFSILY--DPDETLNFIAPNKYEYCIWIDGVNALLG 667
Cdd:pfam16457  81 SG-KKSKKTSSTLAFSLIYgaDEYELLDFVAPSESVAAIWLDGLNMLLG 128

Engulfment and cell motility protein 1 pleckstrin homology (PH) domain; DOCK2 (Dedicator of cytokinesis 2), a hematopoietic cell-specific, atypical GEF, controls lymphocyte migration through Rac activation. A DOCK2-ELMO1 complex s necessary for DOCK2-mediated Rac signaling. DOCK2 contains a SH3 domain at its N-terminus, followed by a lipid binding DHR1 domain, and a Rac-binding DHR2 domain at its C-terminus. ELMO1, a mammalian homolog of C. elegans CED-12, contains the N-terminal RhoG-binding region, the ELMO domain, the PH domain, and the C-terminal sequence with three PxxP motifs. The C-terminal region of ELMO1, including the Pro-rich sequence, binds the SH3-containing region of DOCK2 forming a intermolecular five-helix bundle along with the PH domain of ELMO1. Autoinhibition of ELMO1 and DOCK2 is accomplished by the interactions of the EID and EAD domains and SH3 and DHR2 domains, respectively. The interaction of DOCK2 and ELMO1 mutually relieve their autoinhibition and results in the activation of Rac1. The PH domain of ELMO1 does not bind phosphoinositides due to the absence of key binding residues. It more closely resembles the FERM domain rather than other PH domains. 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 56118506 539 ELIKQQRLNRLCEGSSFRKTGNRRRQERFWFCRLALNHKVLHYGDLEDNVQGEvPYESLQEKIPVSDIKAVVTGKDCPHM 618
Cdd:cd13359   1 ELIKQQRLNFLVEGTLFPKYNARGRKDKFWYCRLSPNHKVLHYGDCEESAQPA-PLEELPEKLPVADIKALVTGKDCPHM 79

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 56118506 619 KEKSAlkqNKEVLELAFSILYDPDETLNFIAPNKYEYCIWIDGVNALLGR 668
Cdd:cd13359  80 KELKK---NKSVASLAFSILYDSDESLDFVAPNETVFDIWTDGLNALLGK 126

Pleckstrin homology domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 56118506   541 IKQQRLNRLCEGSSFRKTGNRRRQERFWFCRLALNHKVLHYGDLEDNVQGEVPYESLQEKIPVSDIKAVVTGKDCPHMKE 620
Cdd:pfam16457   1 VKEQRLNCLLEGAWFPKVRGRRRKKKYRFCRLSPNRKVLHYGDFEEKPTVDPSLESLPEKIDLSDIKEVVTGKECPHVRE 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 56118506   621 KSaLKQNKEVLELAFSILY--DPDETLNFIAPNKYEYCIWIDGVNALLG 667
Cdd:pfam16457  81 SG-KKSKKTSSTLAFSLIYgaDEYELLDFVAPSESVAAIWLDGLNMLLG 128

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 56118506    557 KTGNRRRQERFWFcrlaLNHKVLHYGDLEDNVQGEVPyeslQEKIPVSDIKaVVTGKDCPHMKEKsalkqnkevleLAFS 636
Cdd:smart00233  12 GGGKKSWKKRYFV----LFNSTLLYYKSKKDKKSYKP----KGSIDLSGCT-VREAPDPDSSKKP-----------HCFE 71

                           90       100       110
                   ....*....|....*....|....*....|
gi 56118506    637 ILYDPDETLNFIAPNKYEYCIWIDGVNALL 666
Cdd:smart00233  72 IKTSDRKTLLLQAESEEEREKWVEALRKAI 101

Phospholipase C-eta (PLC-eta) pleckstrin homology (PH) domain; PLC-eta (PLCeta) consists of two enzymes, PLCeta1 and PLCeta2. They hydrolyze phosphatidylinositol 4,5-bisphosphate, are more sensitive to Ca2+ than other PLC isozymes, and involved in PKC activation in the brain and neuroendocrine systems. PLC-eta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves by a variable linker, a C2 domain, and a C-terminal PDZ domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). 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.involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. 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 kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 56118506 600 KIPVSDIKAVVTGKDCPHMKEKSALKQNKEvlELAFSILY-DPDETLNFIAPNKYEYCIWIDGVNALL 666
Cdd:cd13364  43 KIPISSIREVREGKTTDIFRSCDISGDFPE--ECCFSIIYgEEYETLDLVASSPDEANIWITGLRYLM 108