Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein

• Published in: International journal of molecular sciences 2022-10, Vol.23 (21), p.12764
• Main Authors: Weiss, Sandra, Adolph, Ramona S., Schweimer, Kristian, DiFonzo, Andrea, Meleshin, Marat, Schutkowski, Mike, Steegborn, Clemens
• Format: Article
• Language: English
• Subjects: activator; Adaptation; Aging; Binding; Circadian rhythms; Crystal structure; deacetylase; Drug development; Gene expression; Glycerol; Histones; Huntingtons disease; inhibitor; Isoforms; Ligands; Lysine; Magnetic resonance spectroscopy; Mammals; Mass spectrometry; Mass spectroscopy; Metabolism; NMR; NMR spectroscopy; Nuclear magnetic resonance; Peptides; Physiology; Proteins; Psoriasis; regulation; Regulatory proteins; Sirt1; SIRT1 protein; Spectrum analysis; Stress response; Therapeutic targets; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232112764

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’s 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.