8bbk | pdb_00008bbk
Crystal structure of human Sirt3 in complex with a fragment of the human AROS protein
Structural highlights
FunctionSIR3_HUMAN NAD-dependent protein deacetylase. Activates mitochondrial target proteins, including ACSS1, IDH2 and GDH by deacetylating key lysine residues. Contributes to the regulation of the cellular energy metabolism. Important for regulating tissue-specific ATP levels.[1] [2] [3] [4] Publication Abstract from PubMedThe 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. Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein.,Weiss S, Adolph RS, Schweimer K, DiFonzo A, Meleshin M, Schutkowski M, Steegborn C Int J Mol Sci. 2022 Oct 23;23(21):12764. doi: 10.3390/ijms232112764. PMID:36361557[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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