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BBB seminar: Angela M. Gronenborn

Allosteric regulation of the insulin-responsive sensor in the mammalian sirtuin SIRT1

Angela M. Gronenborn
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

SIRT1 is a type III histone deacetylase, containing a conserved catalytic domain with NAD+ dependent enzymatic activity. In addition, it possesses unique features, such as long N- and C-terminal extensions of largely unknown function. We identified an insulin-responsive sensor in the SIRT1 N-terminal region, comprising an acidic cluster (AC) and a 3-helix bundle (3HB), controlling deacetylase activity. Several cellular proteins are involved in the allosteric regulation: the assistor DBC1 removes a distal N-terminal shield from the 3HB, permitting another protein, PACS-2, to engage the AC and the transiently exposed helix 3 of the 3HB, disrupting its structure and inhibiting catalysis. The SIRT1 activator (STAC) SRT1720 binds and stabilizes the 3HB, protecting SIRT1 from inhibition by PACS-2. Identification of the SIRT1 insulin-responsive sensor and its engagement by the DBC1/PACS-2 regulatory hub provides important insight into the roles of disordered regions in enzyme regulation and the mode by which STACs promote metabolic fitness.

Chairperson: Aurora Martinez, Department of Biomedicine

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