| MYST protein acetyltransferase activity requires active site lysine autoacetylation. | |
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MedLine Citation:
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PMID: 22020126 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The MYST protein lysine acetyltransferases are evolutionarily conserved throughout eukaryotes and acetylate proteins to regulate diverse biological processes including gene regulation, DNA repair, cell-cycle regulation, stem cell homeostasis and development. Here, we demonstrate that MYST protein acetyltransferase activity requires active site lysine autoacetylation. The X-ray crystal structures of yeast Esa1 (yEsa1/KAT5) bound to a bisubstrate H4K16CoA inhibitor and human MOF (hMOF/KAT8/MYST1) reveal that they are autoacetylated at a strictly conserved lysine residue in MYST proteins (yEsa1-K262 and hMOF-K274) in the enzyme active site. The structure of hMOF also shows partial occupancy of K274 in the unacetylated form, revealing that the side chain reorients to a position that engages the catalytic glutamate residue and would block cognate protein substrate binding. Consistent with the structural findings, we present mass spectrometry data and biochemical experiments to demonstrate that this lysine autoacetylation on yEsa1, hMOF and its yeast orthologue, ySas2 (KAT8) occurs in solution and is required for acetylation and protein substrate binding in vitro. We also show that this autoacetylation occurs in vivo and is required for the cellular functions of these MYST proteins. These findings provide an avenue for the autoposttranslational regulation of MYST proteins that is distinct from other acetyltransferases but draws similarities to the phosphoregulation of protein kinases. |
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Authors:
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Hua Yuan; Dorine Rossetto; Hestia Mellert; Weiwei Dang; Madhusudan Srinivasan; Jamel Johnson; Santosh Hodawadekar; Emily C Ding; Kaye Speicher; Nebiyu Abshiru; Rocco Perry; Jiang Wu; Chao Yang; Y George Zheng; David W Speicher; Pierre Thibault; Alain Verreault; F Bradley Johnson; Shelley L Berger; Rolf Sternglanz; Steven B McMahon; Jacques Côté; Ronen Marmorstein |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-10-21 |
Journal Detail:
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Title: The EMBO journal Volume: 31 ISSN: 1460-2075 ISO Abbreviation: EMBO J. Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-01-04 Completed Date: 2012-04-27 Revised Date: 2013-05-23 |
Medline Journal Info:
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Nlm Unique ID: 8208664 Medline TA: EMBO J Country: England |
Other Details:
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Languages: eng Pagination: 58-70 Citation Subset: IM |
Affiliation:
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Gene Expression and Regulation Program, The Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/3T06; 3T07; 3T09; 3TOA; 3TOB |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Binding Sites Catalytic Domain Crystallography, X-Ray Histone Acetyltransferases / genetics, metabolism* Histones / metabolism Humans Lysine / genetics* Saccharomyces cerevisiae Proteins / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AG031862/AG/NIA NIH HHS; CA 010815/CA/NCI NIH HHS; CA090465/CA/NCI NIH HHS; CA098172/CA/NCI NIH HHS; GM060293/GM/NIGMS NIH HHS; GM086717/GM/NIGMS NIH HHS; GM55641/GM/NIGMS NIH HHS; GM88297/GM/NIGMS NIH HHS; MOP-14308//Canadian Institutes of Health Research; P30 CA010815/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Histones; 0/Saccharomyces cerevisiae Proteins; 56-87-1/Lysine; EC 2.3.1.48/Esa1 protein, S cerevisiae; EC 2.3.1.48/Histone Acetyltransferases; EC 2.3.1.48/KAT8 protein, human; EC 2.3.1.48/Sas2 protein, S cerevisiae |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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