Friday, July 4, 2025 7/4/2025

Impact of ALS-linked mutations on the structure, dynamics and function of profilin-1

Award Number: R01GM137529
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: 01/08/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2024

Group Awards By:

View Award Description

Impact of ALS-linked mutations on the structure, dynamics and function of profilin-1 - MASSI/ BOSCO – ABSTRACT Profilin-1 (PFN1) is a 15kDa actin-binding protein that plays a critical role in regulating cytoskeletal dynamics. In order to promote actin polymerization in cells, PFN1-bound actin must bind and synergize with formin proteins. In 2012, we identified mutations in PFN1 that cause the uniformly lethal neurodegenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Defects in cytoskeletal dynamics and trafficking were already implicated in ALS pathogenesis, however the mechanism(s) by which ALS-linked proteins disrupt these processes is poorly understood. Many in the field predicted that ALS-linked mutations in PFN1 would abrogate the binding of PFN1 to other cytoskeletal proteins, such as actin and/or members of the formin family of proteins. However, rather unexpectedly, our extensive preliminary data show the opposite. ALS-linked PFN1 (ALS-PFN1) exhibits enhanced binding affinity for select formin proteins in cells and in vitro. Further, ALS-PFN1 causes formins to become hyperactivated, leading to accelerated and greater actin polymerization in cells. Our previous biochemical analyses demonstrated that ALS-PFN1 variants are severely destabilized and prone to aggregate. However, the overall three-dimensional x-ray structures of PFN1 mutants are very similar to WT PFN1. Therefore, we hypothesize that altered protein dynamics caused by ALS- mutations account for our observed phenotypes with respect to formin binding, actin polymerization and PFN1 aggregation. To test this hypothesis, Drs. Francesca Massi and Daryl Bosco have formed a multi- disciplinary, collaborative project that combines molecular dynamics (MD), NMR, fluorescence spectroscopy and cell biology to study the interactions of PFN1 with both formins and actin at atomistic resolution. Indeed, our novel preliminary MD simulations indicate that ALS-linked mutations perturb a network of residues within PFN1 that contact both actin and formin. Further, our extensive preliminary NMR data reveal PFN1 residues near the formin-binding interface are affected by actin binding, and that ALS-linked mutations perturb the intrinsic dynamics of PFN1. Collectively, our preliminary data provide a strong premise that altered protein dynamics of ALS-PFN1 contributes to dysregulated actin polymerization and protein aggregation, which are both involved in ALS pathogenesis. Our proposal builds upon our exciting preliminary data to rigorously characterize the dynamics and mechanism(s) of binding between PFN1, actin and formin. These approaches are highly innovative in the context of studying actin dynamics, and are ideal for probing the actin-PFN1-formin ternary complex, for which little is known at atomistic resolution. These studies are expected to have a significant and broad impact on neurodegenerative disease research, as well as on our fundamental understanding of actin dynamics.


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 = $0 )
2025	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	4	4/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $521,114 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	4	11/16/2023	NON-COMPETING CONTINUATION	$469,003
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	4	6/18/2024	NON-COMPETING CONTINUATION	$52,111
														Subtotal = $521,114

Issue Date FY: 2023 ( Subtotal = $521,114 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	3	3/10/2023	NON-COMPETING CONTINUATION	$52,111
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	3	11/15/2022	NON-COMPETING CONTINUATION	$469,003
														Subtotal = $521,114

Issue Date FY: 2022 ( Subtotal = $521,114 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	2	11/30/2021	NON-COMPETING CONTINUATION	$469,003
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	001	2	7/28/2022	NON-COMPETING CONTINUATION	$52,111
														Subtotal = $521,114

Issue Date FY: 2021 ( Subtotal = $507,572 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Biomedical Research and Research Training	000	1	12/31/2020	NEW	$507,572
														Subtotal = $507,572

Grand Total All Awards = $2,070,914

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Impact of ALS-linked mutations on the structure, dynamics and function of profilin-1

Award Number: R01GM137529

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: 01/08/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2024

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer