|
|
| (One intermediate revision not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Crystal structure of PLEKHM1 LIR-fused human LC3A_2-121== | | ==Crystal structure of PLEKHM1 LIR-fused human LC3A_2-121== |
| - | <StructureSection load='5dpr' size='340' side='right' caption='[[5dpr]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='5dpr' size='340' side='right'caption='[[5dpr]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5dpr]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DPR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DPR FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5dpr]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DPR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DPR FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3x0w|3x0w]], [[5dps|5dps]], [[5dpt|5dpt]], [[5dpw|5dpw]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP1LC3A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5dpr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dpr OCA], [https://pdbe.org/5dpr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dpr RCSB], [https://www.ebi.ac.uk/pdbsum/5dpr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dpr ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5dpr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dpr OCA], [http://pdbe.org/5dpr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dpr RCSB], [http://www.ebi.ac.uk/pdbsum/5dpr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dpr ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/PKHM1_HUMAN PKHM1_HUMAN]] Intermediate osteopetrosis. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/PKHM1_HUMAN PKHM1_HUMAN] Intermediate osteopetrosis. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PKHM1_HUMAN PKHM1_HUMAN]] Proposed to act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Seems to be involved in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Involved in vesicular transport in the osteoclast (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7 (PubMed:25500191).[UniProtKB:Q5PQS0]<ref>PMID:12820725</ref> <ref>PMID:20943950</ref> <ref>PMID:25498145</ref> <ref>PMID:25500191</ref> | + | [https://www.uniprot.org/uniprot/MLP3A_HUMAN MLP3A_HUMAN] Involved in formation of autophagosomal vacuoles (autophagosomes).[https://www.uniprot.org/uniprot/PKHM1_HUMAN PKHM1_HUMAN] Proposed to act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Seems to be involved in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Involved in vesicular transport in the osteoclast (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7 (PubMed:25500191).[UniProtKB:Q5PQS0]<ref>PMID:12820725</ref> <ref>PMID:20943950</ref> <ref>PMID:25498145</ref> <ref>PMID:25500191</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Through the canonical LC3 interaction motif (LIR), [W/F/Y]-X1-X2-[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30 known core LIR motifs towards individual LC3s and GABARAPs. From these, we define a G ABARAP I nteraction M otif (GIM) sequence ([W/F]-[V/I]-X2-V) that the adaptor protein PLEKHM1 tightly conforms to. Using biophysical and structural approaches, we show that the PLEKHM1-LIR is indeed 11-fold more specific for GABARAP than LC3B. Selective mutation of the X1 and X2 positions either completely abolished the interaction with all LC3 and GABARAPs or increased PLEKHM1-GIM selectivity 20-fold towards LC3B. Finally, we show that conversion of p62/SQSTM1, FUNDC1 and FIP200 LIRs into our newly defined GIM, by introducing two valine residues, enhances their interaction with endogenous GABARAP over LC3B. The identification of a GABARAP-specific interaction motif will aid the identification and characterization of the expanding array of autophagy receptor and adaptor proteins and their in vivo functions.
| + | |
| - | | + | |
| - | Structural and functional analysis of the GABARAP interaction motif (GIM).,Rogov VV, Stolz A, Ravichandran AC, Rios-Szwed DO, Suzuki H, Kniss A, Lohr F, Wakatsuki S, Dotsch V, Dikic I, Dobson RC, McEwan DG EMBO Rep. 2017 Aug;18(8):1382-1396. doi: 10.15252/embr.201643587. Epub 2017 Jun, 27. PMID:28655748<ref>PMID:28655748</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5dpr" style="background-color:#fffaf0;"></div>
| + | |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Microtubule-associated protein|Microtubule-associated protein]] | + | *[[Microtubule-associated protein 3D structures|Microtubule-associated protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Dobson, R C.J]] | + | [[Category: Large Structures]] |
| - | [[Category: Ravichandran, A C]] | + | [[Category: Dobson RCJ]] |
| - | [[Category: Suzuki, H]] | + | [[Category: Ravichandran AC]] |
| - | [[Category: Atg8]] | + | [[Category: Suzuki H]] |
| - | [[Category: Autophagy]]
| + | |
| - | [[Category: Chimeric protein]]
| + | |
| - | [[Category: Gabarap]]
| + | |
| - | [[Category: Lc3]]
| + | |
| - | [[Category: Plekhm1]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| Structural highlights
Disease
PKHM1_HUMAN Intermediate osteopetrosis. The disease is caused by mutations affecting the gene represented in this entry.
Function
MLP3A_HUMAN Involved in formation of autophagosomal vacuoles (autophagosomes).PKHM1_HUMAN Proposed to act as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. Required for late stages of endolysosomal maturation, facilitating both endocytosis-mediated degradation of growth factor receptors and autophagosome clearance. Seems to be involved in the terminal maturation of autophagosomes and to mediate autophagosome-lysosome fusion (PubMed:25498145). Involved in vesicular transport in the osteoclast (By similarity). May be involved in negative regulation of endocytic transport from early endosome to late endosome/lysosome implicating its association with Rab7 (PubMed:20943950). May have a role in sialyl-lex-mediated transduction of apoptotic signals (PubMed:12820725). In case of infection contributes to Salmonella typhimurium pathogenesis by supporting the integrity of the Salmonella-containing vacuole (SCV) probably in concert with the HOPS complex and Rab7 (PubMed:25500191).[UniProtKB:Q5PQS0][1] [2] [3] [4]
See Also
References
- ↑ Hartel-Schenk S, Gratchev A, Hanski ML, Ogorek D, Trendelenburg G, Hummel M, Hopfner M, Scherubl H, Zeitz M, Hanski C. Novel adapter protein AP162 connects a sialyl-Le(x)-positive mucin with an apoptotic signal transduction pathway. Glycoconj J. 2001 Nov-Dec;18(11-12):915-23. PMID:12820725
- ↑ Tabata K, Matsunaga K, Sakane A, Sasaki T, Noda T, Yoshimori T. Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain. Mol Biol Cell. 2010 Dec;21(23):4162-72. doi: 10.1091/mbc.E10-06-0495. Epub 2010, Oct 13. PMID:20943950 doi:http://dx.doi.org/10.1091/mbc.E10-06-0495
- ↑ McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, Coxon FP, Miranda de Stegmann D, Bhogaraju S, Maddi K, Kirchof A, Gatti E, Helfrich MH, Wakatsuki S, Behrends C, Pierre P, Dikic I. PLEKHM1 Regulates Autophagosome-Lysosome Fusion through HOPS Complex and LC3/GABARAP Proteins. Mol Cell. 2015 Jan 8;57(1):39-54. doi: 10.1016/j.molcel.2014.11.006. Epub 2014, Dec 11. PMID:25498145 doi:http://dx.doi.org/10.1016/j.molcel.2014.11.006
- ↑ McEwan DG, Richter B, Claudi B, Wigge C, Wild P, Farhan H, McGourty K, Coxon FP, Franz-Wachtel M, Perdu B, Akutsu M, Habermann A, Kirchof A, Helfrich MH, Odgren PR, Van Hul W, Frangakis AS, Rajalingam K, Macek B, Holden DW, Bumann D, Dikic I. PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection. Cell Host Microbe. 2015 Jan 14;17(1):58-71. doi: 10.1016/j.chom.2014.11.011. Epub, 2014 Dec 11. PMID:25500191 doi:http://dx.doi.org/10.1016/j.chom.2014.11.011
|
