Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19113459   2 AFYLETTPSNLPVLDPSEEILLVQDQVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDVQHTSRY 81
Cdd:cd13227   1 WHYVETTRSGQPILRENEKDIYVDDNVGLYHGKSKILNRQNGRIYLTSQRIIYVDDDDPKKNSVALELDDIKSVEYSSGF 80

                        90       100
                ....*....|....*....|....*..
gi 19113459  82 FRSSPKIRLSL-----RHVEKSWACKI 103
Cdd:cd13227  81 LKRSPKIILFLkdesqEGLKKSKNKKI 107

Zinc finger domain; Zinc finger domain in Ran-binding proteins (RanBPs), and other proteins. In RanBPs, this domain binds RanGDP.

                           10        20
                   ....*....|....*....|
gi 19113459    141 CTACTFQNYPDLNTCEICGN 160
Cdd:smart00547   5 CPACTFLNFASRSKCFACGA 24

Pleckstrin homology-like domain or GLUE (GRAM-like ubiquitin-binding in Eap45) domain of Vps36; ESCRT complexes form the main machinery driving protein sorting from endosomes to lysosomes. Yeast/human ESCRT-I consists of Vps23/Tsg101, Vps28/Vps28, and Vps37/Vps37 homolog. Yeast/human ESCRT-II is composed of Vps25/EAP20, Vps22/EAP30, and Vps36/EAP45. Yeast ESCRT-III consists Vps2, Vps20, Vps24, and Snf7 subunits. In contrast, there are three human paralogs of Snf7 (hSnf7-1/CHMP4A, hSnf7-2/CHMP4B, and hSnf7-3/CHMP4C) and two paralogs of Vps2 (CHMP2A and CHMP2B). Yeast ESCRT-I links directly to ESCRT-II, through a tight interaction of Vps28 (ESCRT-I) with the yeast-specific zinc-finger insertion within the GLUE domain of Vps36. The Vps36 subunit (ESCRT-II) binds ubiquitin using one of its two NZF zinc fingers in its N-terminal region. Human Vps36, EAP45, also binds ubiquitin despite having no NZF domain. Instead, mammalian ESCRT-II interacts with Ub through the Eap45 GLUE domain itself. The yeast Vps36 GLUE has a complete PH domain, wherease Eap45 GLUE only has a PH-like fold since it lacks the secondary structure element corresponding to the 4 strand. ESCRT-II also interacts with ESCRT-III via a Vps25(EAP20)/Vps20(CHMP6) interaction. Structure 2CAY is missing this insertion that contains 2 NZF zinc fingers. It is a split PH domain, with a noncanonical lipid binding pocket that binds PI(3)P. The interactions of ESCRT-II GLUE domain with membranes, ESCRT-I, and ubiquitin are critical for ubiquitinated cargo progression from early to late endosomes. 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 19113459   2 AFYLETTPSNLPVLDPSEEILLVQDQVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDVQHTSRY 81
Cdd:cd13227   1 WHYVETTRSGQPILRENEKDIYVDDNVGLYHGKSKILNRQNGRIYLTSQRIIYVDDDDPKKNSVALELDDIKSVEYSSGF 80

                        90       100
                ....*....|....*....|....*..
gi 19113459  82 FRSSPKIRLSL-----RHVEKSWACKI 103
Cdd:cd13227  81 LKRSPKIILFLkdesqEGLKKSKNKKI 107

Vacuolar protein sorting protein 36 Vps36; Vps36 is a subunit of ESCRT-II, a protein involved in driving protein sorting from endosomes to lysosomes. The GLUE domain of Vps36 allows for a tight interaction to occur between the protein and Vps28, a subunit of ESCRT-I. This interaction is critical for ubiquitinated cargo progression from early to late endosomes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19113459     6 ETTPSNLPVLDPSEEILLVQDQVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDV---QHTSRYF 82
Cdd:pfam11605   1 ERNTSGRPVLRENEVDIYVQDNVGLYQGDQKILNRQNGRLYLTTHRIIYVDSADPKKVSLSLPLKLVYSIsekEYSSGFL 80

                          90
                  ....*....|..
gi 19113459    83 RSSPKIRLSLRH 94
Cdd:pfam11605  81 RSSPKIILFLKP 92

Vacuolar protein sorting 36 NZF-N zinc-finger domain; The vacuolar protein sorting 36 NZF-N zinc-finger domain interacts with the C-terminus of vacuolar protein sorting 28.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 19113459    99 WACKICTF---------INVGDPINPCRNCGVANRFTIIK 129
Cdd:pfam16988  10 WVCPICSFsnpvpsnfdPNASTPLPPCLACGIKPDFELIK 49

Pleckstrin homology-like domain or GLUE (GRAM-like ubiquitin-binding in Eap45) domain of Vps36; ESCRT complexes form the main machinery driving protein sorting from endosomes to lysosomes. Yeast/human ESCRT-I consists of Vps23/Tsg101, Vps28/Vps28, and Vps37/Vps37 homolog. Yeast/human ESCRT-II is composed of Vps25/EAP20, Vps22/EAP30, and Vps36/EAP45. Yeast ESCRT-III consists Vps2, Vps20, Vps24, and Snf7 subunits. In contrast, there are three human paralogs of Snf7 (hSnf7-1/CHMP4A, hSnf7-2/CHMP4B, and hSnf7-3/CHMP4C) and two paralogs of Vps2 (CHMP2A and CHMP2B). Yeast ESCRT-I links directly to ESCRT-II, through a tight interaction of Vps28 (ESCRT-I) with the yeast-specific zinc-finger insertion within the GLUE domain of Vps36. The Vps36 subunit (ESCRT-II) binds ubiquitin using one of its two NZF zinc fingers in its N-terminal region. Human Vps36, EAP45, also binds ubiquitin despite having no NZF domain. Instead, mammalian ESCRT-II interacts with Ub through the Eap45 GLUE domain itself. The yeast Vps36 GLUE has a complete PH domain, wherease Eap45 GLUE only has a PH-like fold since it lacks the secondary structure element corresponding to the 4 strand. ESCRT-II also interacts with ESCRT-III via a Vps25(EAP20)/Vps20(CHMP6) interaction. Structure 2CAY is missing this insertion that contains 2 NZF zinc fingers. It is a split PH domain, with a noncanonical lipid binding pocket that binds PI(3)P. The interactions of ESCRT-II GLUE domain with membranes, ESCRT-I, and ubiquitin are critical for ubiquitinated cargo progression from early to late endosomes. 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 19113459   2 AFYLETTPSNLPVLDPSEEILLVQDQVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDVQHTSRY 81
Cdd:cd13227   1 WHYVETTRSGQPILRENEKDIYVDDNVGLYHGKSKILNRQNGRIYLTSQRIIYVDDDDPKKNSVALELDDIKSVEYSSGF 80

                        90       100
                ....*....|....*....|....*..
gi 19113459  82 FRSSPKIRLSL-----RHVEKSWACKI 103
Cdd:cd13227  81 LKRSPKIILFLkdesqEGLKKSKNKKI 107

Vacuolar protein sorting protein 36 Vps36; Vps36 is a subunit of ESCRT-II, a protein involved in driving protein sorting from endosomes to lysosomes. The GLUE domain of Vps36 allows for a tight interaction to occur between the protein and Vps28, a subunit of ESCRT-I. This interaction is critical for ubiquitinated cargo progression from early to late endosomes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 19113459     6 ETTPSNLPVLDPSEEILLVQDQVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDV---QHTSRYF 82
Cdd:pfam11605   1 ERNTSGRPVLRENEVDIYVQDNVGLYQGDQKILNRQNGRLYLTTHRIIYVDSADPKKVSLSLPLKLVYSIsekEYSSGFL 80

                          90
                  ....*....|..
gi 19113459    83 RSSPKIRLSLRH 94
Cdd:pfam11605  81 RSSPKIILFLKP 92

Vacuolar protein sorting 36 NZF-N zinc-finger domain; The vacuolar protein sorting 36 NZF-N zinc-finger domain interacts with the C-terminus of vacuolar protein sorting 28.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 19113459    99 WACKICTF---------INVGDPINPCRNCGVANRFTIIK 129
Cdd:pfam16988  10 WVCPICSFsnpvpsnfdPNASTPLPPCLACGIKPDFELIK 49

Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain; Myotubularin-related proteins are a subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in this family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. 6 of the 13 MTMRs (MTMRs 5, 9-13) contain naturally occurring substitutions of residues required for catalysis by PTP family enzymes. Although these proteins are predicted to be enzymatically inactive, they are thought to function as antagonists of endogenous phosphatase activity or interaction modules. Most MTMRs contain a N-terminal PH-GRAM domain, a Rac-induced recruitment domain (RID) domain, a PTP domain (which may be active or inactive), a SET-interaction domain, and a C-terminal coiled-coil region. In addition some members contain DENN domain N-terminal to the PH-GRAM domain and FYVE, PDZ, and PH domains C-terminal to the coiled-coil region. The GRAM domain, found in myotubularins, glucosyltransferases, and other putative membrane-associated proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 19113459  27 QVGLYFGDEKSFRHNNGTLYLTKKHIFYVDSVDPKKNSLKIKISDIRDVQHTSRYFRSSPKI 88
Cdd:cd10570   5 GVRFCCALRPRKLPLEGTLYLSTYRLIFSSKADGDETKLVIPLVDITDVEKIAGASFLPSGL 66