{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:01:10Z","timestamp":1791198070066,"version":"4.1.0"},"reference-count":40,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,23]],"date-time":"2022-10-23T00:00:00Z","timestamp":1666483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["STE1701\/15"],"award-info":[{"award-number":["STE1701\/15"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The protein lysine deacylases of the NAD+-dependent Sirtuin family contribute to metabolic regulation, stress responses, and aging processes, and the human Sirtuin isoforms, Sirt1-7, are considered drug targets for aging-related diseases. The nuclear isoform Sirt1 deacetylates histones and transcription factors to regulate, e.g., metabolic adaptations and circadian mechanisms, and it is used as a therapeutic target for Huntington\u2019s disease and psoriasis. Sirt1 is regulated through a multitude of mechanisms, including the interaction with regulatory proteins such as the inhibitors Tat and Dbc1 or the activator AROS. Here, we describe a molecular characterization of AROS and how it regulates Sirt1. We find that AROS is a partly intrinsically disordered protein (IDP) that inhibits rather than activates Sirt1. A biochemical characterization of the interaction including binding and stability assays, NMR spectroscopy, mass spectrometry, and a crystal structure of Sirtuin\/AROS peptide complex reveal that AROS acts as a competitive inhibitor, through binding to the Sirt1 substrate peptide site. Our results provide molecular insights in the physiological regulation of Sirt1 by a regulator protein and suggest the peptide site as an opportunity for Sirt1-targeted drug development.<\/jats:p>","DOI":"10.3390\/ijms232112764","type":"journal-article","created":{"date-parts":[[2022,10,24]],"date-time":"2022-10-24T04:40:36Z","timestamp":1666586436000},"page":"12764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein"],"prefix":"10.3390","volume":"23","author":[{"given":"Sandra","family":"Weiss","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5143-5977","authenticated-orcid":false,"given":"Ramona S.","family":"Adolph","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3837-8442","authenticated-orcid":false,"given":"Kristian","family":"Schweimer","sequence":"additional","affiliation":[{"name":"Department of Biopolymers, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"DiFonzo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marat","family":"Meleshin","sequence":"additional","affiliation":[{"name":"Department of Enzymology, Charles Tanford Protein Center, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike","family":"Schutkowski","sequence":"additional","affiliation":[{"name":"Department of Enzymology, Charles Tanford Protein Center, Institute for Biochemistry and Biotechnology, Martin Luther University Halle-Wittenberg, 06108 Halle (Saale), Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0913-1467","authenticated-orcid":false,"given":"Clemens","family":"Steegborn","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1038\/ncomms3327","article-title":"An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms","volume":"4","author":"Rauh","year":"2013","journal-title":"Nat. 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