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Mechanism of activation for the sirtuin 6 protein deacylase

The Journal of biological chemistry, 2020-01, Vol.295 (5), p.1385-1399 [Peer Reviewed Journal]

2020 Klein et al. 2020 Klein et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA119.011285 ;PMID: 31822559

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  • Title:
    Mechanism of activation for the sirtuin 6 protein deacylase
  • Author: Klein, Mark A. ; Liu, Can ; Kuznetsov, Vyacheslav I. ; Feltenberger, John B. ; Tang, Weiping ; Denu, John M.
  • Subjects: Editors' Picks
  • Is Part Of: The Journal of biological chemistry, 2020-01, Vol.295 (5), p.1385-1399
  • Description: The histone deacetylase sirtuin 6 (SIRT6) regulates numerous biological functions, including transcriptional repression, DNA repair, and telomere maintenance. Recombinant SIRT6 displays catalytic efficiencies 2 orders of magnitude greater for long-chain deacylation than deacetylation against peptide substrates; however, deacetylation can be enhanced by allosteric small-molecule activators. Here, we investigated the mechanisms of activated lysine deacetylation and enhanced long-chain acyl-group removal by SIRT6. Activity-based screening identified compounds that activated histone peptide deacetylation 18-48-fold. Chemical optimization based on structure–activity relationships yielded an activator with improved potency and selectivity for SIRT6. Using this novel activator, we conducted biochemical and kinetic analyses revealing that SIRT6 is activated via acceleration of a catalytic step occurring after substrate binding but before NAD + cleavage. We identified a SIRT6 variant, R65A, that maintains basal deacetylase activity but cannot be activated and failed to enhance long-chain deacylation. Additional biochemical studies revealed that Arg-65 is critical for activation by facilitating a conformational step that initiates chemical catalysis. This work suggests that SIRT6 activation of deacetylation involves a similar mechanism to improved catalysis as that of long-chain deacylation. The identification of novel SIRT6 activators and the molecular insights into activation and catalysis presented here provide a foundational understanding for physiological SIRT6 activation and for rational design of activating molecules.
  • Publisher: 11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A: American Society for Biochemistry and Molecular Biology
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1074/jbc.RA119.011285
    PMID: 31822559
  • Source: PubMed Central
    Alma/SFX Local Collection
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