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Intramolecular Allosteric Regulation of SIRT1 Deacetylase Activity by the N-terminal Domain

Award Number: SC2GM132000
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: 06/13/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Intramolecular Allosteric Regulation of SIRT1 Deacetylase Activity by the N-terminal Domain - Project Summary This project aims to elucidate the mechanism for intramolecular regulation of SIRT1 activity by 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, where the regulation of SIRT1 activity could combat diseases such as diabetes, cancer and neurodegenerative diseases. 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 a complicated role 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 on the N-terminal domain and its role in SIRT1 mechanism. Our project is focused on understanding the allosteric interactions between the N-terminal domain and SIRT1’s catalytic core using three independent aims that focus on conformational changes, specific key residues and binding events. Various structures of SIRT1 complexed with different ligands have shown the SBD in different orientations, suggesting a conformational flexibility of this domain. However, detailed studies linking the N-terminal domain conformation with enzyme activity are lacking. We will study this relationship by taking advantage of the substrate-specific SIRT1 regulator, resveratrol (Aim 1). A distinct allosteric switch region within the N-terminal of SIRT1 has yet to be experimentally defined. To this end, we will identify allosteric switch regions within the SIRT1 N-terminal domain (Aim 2). Additionally, an intrinsically unstructured region in the N-terminal domain, motif A, has been shown to bind to the SBD and potentiate SIRT1 activity as well, but the interaction parameters such as dissociation equilibrium constants have not been defined. We will further investigate this binding interaction in vitro and study the effects of phosphorylation at motif A on its ability to affect SIRT1 activity (Aim 3). 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. It would also provide insight into how other allosterically regulated enzymes function in the cell.


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: 2024 ( Subtotal = -$5,815 )
2024	2021	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	12/5/2023	NON-COMPETING CONTINUATION	-$5,815
														Subtotal = -$5,815

Issue Date FY: 2021 ( Subtotal = $144,500 )
2021	2021	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	5/20/2021	NON-COMPETING CONTINUATION	$144,500
														Subtotal = $144,500

Issue Date FY: 2020 ( Subtotal = $138,960 )
2020	2020	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	5/19/2020	NON-COMPETING CONTINUATION	$138,960
														Subtotal = $138,960

Issue Date FY: 2019 ( Subtotal = $131,546 )
2019	2019	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	6/13/2019	NEW	$131,546
														Subtotal = $131,546

Grand Total All Awards = $409,191

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Intramolecular Allosteric Regulation of SIRT1 Deacetylase Activity by the N-terminal Domain

Award Number: SC2GM132000

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: 06/13/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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