International Journal of Molecular Sciences (Oct 2022)

Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein

  • Sandra Weiss,
  • Ramona S. Adolph,
  • Kristian Schweimer,
  • Andrea DiFonzo,
  • Marat Meleshin,
  • Mike Schutkowski,
  • Clemens Steegborn

DOI
https://doi.org/10.3390/ijms232112764
Journal volume & issue
Vol. 23, no. 21
p. 12764

Abstract

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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.

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