{"corpus_id":4362465,"paper_sha":"6dad189c689fa12439b389558508b38829c06798","doi":"10.1016/j.str.2017.05.020","arxiv_id":null,"pmid":28648608,"pmcid":"5501728","mag_id":2646893109,"dblp_id":null,"acl_id":null,"title":"Structures of PGAM5 Provide Insight into Active Site Plasticity and Multimeric Assembly","year":2017,"publication_date":"2017-07-05","venue":"Structure","journal":{"name":"Structure(London, England:1993)","pages":"1089 - 1099.e3","volume":"25"},"journal_issn":null,"journal_title":null,"publication_types":["JournalArticle"],"pubmed_pub_types":["Journal Article","Research Support, Non-U.S. Gov't"],"s2_fields_of_study":["Biology","Medicine","Chemistry"],"reference_count":44,"citation_count":42,"influential_citation_count":4,"is_open_access":true,"arxiv_categories":null,"arxiv_license":null,"arxiv_journal_ref":null,"mesh_headings":[{"d":"Allosteric Regulation","mj":false,"ui":"D000494"},{"d":"Allosteric Site","mj":false,"ui":"D000495"},{"d":"Catalytic Domain","mj":true,"ui":"D020134"},{"d":"HEK293 Cells","mj":false,"ui":"D057809"},{"d":"Humans","mj":false,"ui":"D006801"},{"d":"Mitochondrial Proteins","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D024101"},{"d":"Molecular Dynamics Simulation","mj":true,"ui":"D056004"},{"d":"Phosphoprotein Phosphatases","mj":false,"qs":[{"q":"chemistry","mj":true,"ui":"Q000737"},{"q":"metabolism","mj":false,"ui":"Q000378"}],"ui":"D010749"},{"d":"Protein Multimerization","mj":true,"ui":"D055503"}],"chemicals":[{"n":"Mitochondrial Proteins","ui":"D024101","reg":"0"},{"n":"PGAM5 protein, human","ui":"C529563","reg":"EC 3.1.3.16"},{"n":"Phosphoprotein Phosphatases","ui":"D010749","reg":"EC 3.1.3.16"}],"comments_corrections":null,"source_flags":5,"s2_open_access_pdf_url":"http://www.cell.com/article/S0969212617301545/pdf","s2_open_access_landing_url":"https://www.semanticscholar.org/paper/6dad189c689fa12439b389558508b38829c06798","s2_open_access_license":"CCBY","s2_open_access_status":"HYBRID","pmc_open_access_pdf_url":null,"pmc_open_access_landing_url":null,"pmc_open_access_license":null,"pmc_open_access_status":null,"unpaywall_open_access_pdf_url":null,"unpaywall_open_access_landing_url":null,"unpaywall_open_access_license":null,"unpaywall_open_access_status":null,"abstract":"Summary PGAM5 is a mitochondrial membrane protein that functions as an atypical Ser/Thr phosphatase and is a regulator of oxidative stress response, necroptosis, and autophagy. Here we present several crystal structures of PGAM5 including the activating N-terminal regulatory sequences, providing a model for structural plasticity, dimerization of the catalytic domain, and the assembly into an enzymatically active dodecameric form. Oligomeric states observed in structures were supported by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation experiments in solution. We report that the catalytically important N-terminal WDPNWD motif acts as a structural integrator assembling PGAM5 into a dodecamer, allosterically activating the phosphatase by promoting an ordering of the catalytic loop. Additionally the observed active site plasticity enabled visualization of essential conformational rearrangements of catalytic elements. The comprehensive biophysical characterization offers detailed structural models of this key mitochondrial phosphatase that has been associated with the development of diverse diseases.","claims":[{"public_id":"cl_771d7287bc61d2f3a8caa0c95987aa6e","status":"active","text":"Active site plasticity enables visualization of essential conformational rearrangements of catalytic elements.","confidence":0.92,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_771d7287bc61d2f3a8caa0c95987aa6e"},{"public_id":"cl_44560e6a36197050eaf28ac51ead3f7e","status":"active","text":"Oligomeric states observed in the crystal structures are supported in solution by hydrogen exchange mass spectrometry, size-exclusion chromatography, and analytical ultracentrifugation.","confidence":0.95,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_44560e6a36197050eaf28ac51ead3f7e"},{"public_id":"cl_a82c9b3d05430ea0e0a50176a709bc69","status":"active","text":"Several crystal structures of PGAM5, including activating N-terminal regulatory sequences, support a model in which structural plasticity, catalytic-domain dimerization, and assembly into an enzymatically active dodecamer are linked.","confidence":0.97,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_a82c9b3d05430ea0e0a50176a709bc69"},{"public_id":"cl_d2cbe2456b6d7699eca6f0b620eb8d0f","status":"active","text":"The N-terminal WDPNWD motif acts as a structural integrator that assembles PGAM5 into a dodecamer and allosterically activates the phosphatase by promoting ordering of the catalytic loop.","confidence":0.98,"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/claims/cl_d2cbe2456b6d7699eca6f0b620eb8d0f"}],"concepts":[{"public_id":"co_0193df1e463ad7c4a71d44a9b9d10d7a","status":"active","name":"size-exclusion chromatography","description":"A chromatographic method used here to assess the solution behavior of PGAM5 oligomers.","types":["measurement technique"],"aliases":["SEC"],"contributors":[{"id":1,"public_id":"12632b8b5f","public_label":"Anonymous (12632b8b5f)","roles":["extraction"],"url":"https://sah.borca.ai/u/12632b8b5f"}],"url":"https://sah.borca.ai/concepts/co_0193df1e463ad7c4a71d44a9b9d10d7a"},{"public_id":"co_15021aaf11152369fd6879ff645405ef","status":"active","name":"active site plasticity","description":"Flexibility of the PGAM5 active site that permits different conformations of catalytic components.","types":["structural 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