8BBK

Crystal structure of human Sirt3 in complex with a fragment of the human AROS protein

Summary for 8BBK

• Entry DOI: 10.2210/pdb8bbk/pdb
• Descriptor: NAD-dependent protein deacetylase sirtuin-3, mitochondrial, Active regulator of SIRT1, ZINC ION (3 entities in total)
• Functional Keywords: sirtuin 3, peptide complex, aros, inhibitor, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 354974.03

Authors

Steegborn, C.,Weiss, S. (deposition date: 2022-10-13, release date: 2023-08-30)

Primary citation

Weiss, S.,Adolph, R.S.,Schweimer, K.,DiFonzo, A.,Meleshin, M.,Schutkowski, M.,Steegborn, C.
Molecular Mechanism of Sirtuin 1 Modulation by the AROS Protein.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: 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.

PubMed: 36361557
DOI: 10.3390/ijms232112764

Experimental method

X-RAY DIFFRACTION (3.27 Å)