Publication Date

8-18-2026

Document Type

Article

Publication Title

Biochemistry

Volume

65

Issue

16

DOI

10.1021/acs.biochem.6c00333

First Page

2485

Last Page

2494

Abstract

The NAD+-dependent deacetylase sirtuin-1 (SIRT1) is known to elicit cellular defenses against aging, cancer, and other aberrant pathologies. Previous studies have identified an intrinsically disordered region of SIRT1 comprised of N-terminal residues 1–52, herein referred to as motif A, which activates SIRT1 activity, likely through intramolecular interactions. Additionally, phosphorylation of N-terminal residues Ser27 and Ser47 has been shown to be important for regulating SIRT1 activity and stability. The lack of in vitro characterization of these effects hampers our further understanding of the role of motif A in SIRT1 regulation. In this study, we elucidate the role phosphorylation plays in motif A’s structure as well as its regulatory effects on SIRT1 activity against Ac-p65. We find that a phosphomimetic mutation at Ser27 significantly increases the activation effect of motif A toward SIRT1. This result is supported by molecular dynamics simulations of the phosphomimetics, which reveal stabilization of different transient structures for motif A depending on whether Ser27 and Ser47 have been modified. A key finding suggested by this study is that phosphorylation of S27 appears to activate SIRT1 by causing motif A, which is intrinsically disordered in the WT, to become more rigid. This conclusion is based on both the experimental findings and simulation results. While more experiments are necessary to confirm the MD simulation results, these findings still bring us a step closer to understanding SIRT1 regulation, specifically the role played by phosphorylation within the N-terminal disordered region.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Department

Chemistry

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