Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Elucidating the Mechanism for Allosteric Regulation of SIRT1 through the N-terminal Region

Award Number: R16GM149377
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/05/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

Group Awards By:

View Award Description

Elucidating the Mechanism for Allosteric Regulation of SIRT1 through the N-terminal Region - Summary This project aims to elucidate the mechanism for allosteric regulation of SIRT1 activity via the N-terminal domain of SIRT1, a conformationally dynamic region distal to the catalytic core. SIRT1 is an NAD+-dependent protein deacetylase which has been shown to play a significant role in many biological pathways, such as insulin secretion, tumor formation, lipid metabolism and neurodegeneration. For this reason, SIRT1 has been identified as a potential therapeutic target. This progress has been hampered by insufficient understanding of the molecular mechanism of the regulation of SIRT1 activity, as the C-terminal and N-terminal domains within SIRT1 play complicated roles in allosterically affecting SIRT1 activity. The N-terminal domain has been shown to potentiate SIRT1’s enzyme activity; this region also contains the STAC binding domain (SBD), a binding site for sirtuin activating compounds (STACs). However, there is limited in vitro biochemistry study regarding the role of the N-terminal domain in SIRT1 regulation. Our project is focused on understanding the allosteric interactions between the N-terminal domain and SIRT1’s catalytic core using three independent aims as detailed below that focus on the substrate-dependent regulation of SIRT1 by resveratrol, the regulation of SIRT1 by other STACs, and the intramolecular regulation of SIRT1 by motif A, a domain within its N-terminal region. Aim 1: Examine the role of complex stability and conformational dynamics in the substrate-sequence dependent regulation of SIRT1 by resveratrol, a well-studied STAC. We will compare the binding affinity of resveratrol to SIRT1 in the presence of different substrates, compare the stability of different SIRT1•substrate•resveratrol complexes, and compare the conformations of different SIRT1•substrate•resveratrol complexes. Aim 2: Explore if other STACs with similar or different structures as resveratrol can also regulate SIRT1 in a substrate-sequence dependent manner. We will characterize the substrate-sequence dependent effect of other STACs, namely piceatannol and SRT2104 on SIRT1 activity using enzyme activity assays and binding assays. Aim 3: Elucidate the mechanism of intramolecular SIRT1 regulation via motif A, an intrinsically disordered region in the N-terminus of SIRT1 and the role of phosphorylation in this regulation. We will use enzyme activity assays and binding assays, complemented by molecular dynamics simulations, to determine the effects of phosphorylation on motif A’s ability to regulate SIRT1 activity. Our studies will afford a more detailed understanding of the allosteric regulation of SIRT1 elicited by the N- terminal domain. This would clarify how the activity of SIRT1 is altered in various biological pathways and disease states, guiding a more targeted approach in modulating SIRT1 activity as a therapeutic method.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $146,500 )
2025	2025	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	4/18/2025	NON-COMPETING CONTINUATION	$146,500
														Subtotal = $146,500

Issue Date FY: 2024 ( Subtotal = $246,309 )
2024	2024	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	4/30/2024	NON-COMPETING CONTINUATION	$146,500
2024	2024	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	7/12/2024	SUPPLEMENT FOR EXPANSION	$99,809
														Subtotal = $246,309

Issue Date FY: 2023 ( Subtotal = $142,760 )
2023	2023	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	6/5/2023	NEW	$142,760
														Subtotal = $142,760

Grand Total All Awards = $535,569

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Elucidating the Mechanism for Allosteric Regulation of SIRT1 through the N-terminal Region

Award Number: R16GM149377

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/05/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer