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Investigating the mechanism of decision-making in the mitochondrial Protease YME1

Award Number: F31NS136003
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/16/2024
PERIOD OF PERFORMANCE END DATE: 01/15/2026

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Investigating the mechanism of decision-making in the mitochondrial Protease YME1 - PROJECT SUMMARY YME1 is an ATP-dependent protease located in the inner mitochondrial membrane, and plays a central role in executing the functional activities of the mitochondrial protein quality control network. Preserving homeostasis within the mitochondria is critical to maintaining cellular health and preventing a wide range of human diseases resulting from the dysfunction of the mitochondria, including neurodegenerative diseases, cardiovascular disorders, and cancer. YME1 is capable of proteolytically processing a wide variety of diverse mitochondrial substrates through regulatory mechanisms that remain largely unknown. One of the most intriguing aspects of YME1 proteolytic activity arises from its unique ability to perform molecular decision-making: YME1 can choose to perform 1) processive degradation of a target substrate, whereby it cleaves the substrate into small peptides, or 2) site-specific cleavage through which the substrate undergoes a single cleavage event and is subsequently released by YME1. One of the most well-characterized of these site-specific cleavage functions is the cleavage of the optical atrophy 1 (OPA1) protein, which is implicated in age-related eye disease, at an internal loop by the human YME1 protein (YME1L). This cleavage event produces two isoforms of OPA1, the ratio of which is crucial to regulating mitochondrial morphology and function. However, despite much investigation into the mechanistic bases for molecular decision-making performed by YME1 proteins, the atomic drivers that distinguish between these two degradation modes remain elusive. Yeast YME1 shares high sequence conservation with human YME1L, especially at the catalytic sites, making it an excellent molecular model for investigating this substrate processing mechanism. Interestingly, the site-specific cleavage of the yeast chaperone protein Tim10 occurs at a site that shares high sequence conservation with that of human OPA1. Thus, insights gained from studies of proteolytic processing in yeast YME1 have a strong potential to apply broadly to this mechanism in human YME1L as well as related ATP-dependent proteases. This work will focus on elucidating the mechanistic details that define how YME1 selects and distinctly processes protein substrates based on its sequence and folded state. The details of this mechanism will be investigated in two Aims. The first aim will combine structural and biochemical studies to examine how structural components of YME1 perceive and respond to specific sequences within targeted substrates. The second Aim will explore how YME1 switches between processing modalities based on a difference in the folding stability of the targeted substrate. These combined structure-function studies will define the molecular underpinnings that regulate two distinct functional activities of an ATP-dependent protease that are required for mitochondrial health. The outcomes of this study will provide a comprehensive model of the regulation of proteolytic processing by YME1, that will enhance our understanding of human YME1L function, and how perturbations of its function are associated with mitochondrial dysfunction and human disease.


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 = $36,538 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/14/2025	NON-COMPETING CONTINUATION	$564
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/20/2025	NON-COMPETING CONTINUATION	$35,974
														Subtotal = $36,538

Issue Date FY: 2024 ( Subtotal = $35,974 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/8/2024	NEW	$1,280
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/29/2023	NEW	$0
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/29/2023	NEW	$34,694
														Subtotal = $35,974

Grand Total All Awards = $72,512

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Investigating the mechanism of decision-making in the mitochondrial Protease YME1

Award Number: F31NS136003

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/16/2024

PERIOD OF PERFORMANCE END DATE: 01/15/2026

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