# Allosteric regulation of SIRT1 by a PACS-2 and DBC1 regulatory hub

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $643,772

## Abstract

PROJECT SUMMARY
The “nutrient-sensing” enzyme SIRT1 lays at the crossroads of a complex array of molecular interactions that
impact susceptibility to diseases as diverse as obesity, diabetes, neurodegeneration, and cancer. One
promising therapeutic strategy for the treatment of obesity-related morbidity involves small-molecule STACs,
which bind the SIRT1 N-terminal region to allosterically increase SIRT1 activity, thereby elevating the
expression of catabolic PGC-1/PPAR target genes that help to protect against diet-induced obesity. STACs
bind SIRT1 in a 3-helix bundle located at the distal part of the SIRT1 N-terminal region. This 3-helix bundle is
shielded by an upstream element of the SIRT1 N-terminal region, protecting the enzyme from an unidentified
cellular regulator. Thus, identification of cellular proteins that control enzyme activity through interaction with
the 3-helix bundle is key to understanding SIRT1 regulation. Our published and preliminary data suggest
PACS-2 is one such SIRT1 regulator and that PACS-2, DBC1 and SIRT1 form a novel tripartite hub that
controls SIRT1 deacetylase activity. DBC1 binds to the N-terminal region of SIRT1, where it promotes PACS-2
recruitment and binding to SIRT1. PACS-2 destabilizes the critical 3-helix bundle, which inhibits SIRT1 activity
and consequently represses SIRT1-dependent activation of PGC-1/PPAR target genes. Our long-term goal
is to understand how SIRT1 is regulated to control energy homeostasis in humans. The objective of this
particular application is to determine how PACS-2 and DBC1 synergize to allosterically modulate SIRT1
enzyme activity and how this regulatory hub controls the response to fasting or overnutrition in vivo. Our
central hypothesis is that disruption of the SIRT1/PACS-2 or SIRT1/DBC1 interactions will prevent high-fat-
diet-induced repression of SIRT1 and, therefore, protect mice from hepatic steatosis and insulin resistance.
Guided by strong preliminary data, we will test our hypothesis by pursuing three specific aims: 1) Determine
the conformational and mechanistic steps by which the PACS-2/SIRT1 interaction regulates enzyme activity; 2)
Determine how synergistic actions by PACS-2 and DBC1 inhibit SIRT1; and 3) Determine the physiologic
importance of interactions between PACS-2, DBC1, and SIRT1 on hepatic metabolism. The approach is
innovative because it will characterize, from the atomic structure to whole-organism function, a previously
unrecognized regulatory hub controlling energy metabolism during fasting and overnutrition. This research is
significant because it will uncover how SIRT1 regulators control enzyme activity and how we can influence
their functions to improve health.

## Key facts

- **NIH application ID:** 9976499
- **Project number:** 5R01DK114855-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ANGELA M. GRONENBORN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $643,772
- **Award type:** 5
- **Project period:** 2017-08-23 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976499

## Citation

> US National Institutes of Health, RePORTER application 9976499, Allosteric regulation of SIRT1 by a PACS-2 and DBC1 regulatory hub (5R01DK114855-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976499. Licensed CC0.

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