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Molecular mechanism of necroptosis mediated by mixed lineage kinase-like (MLKL) protein

Award Number: R01GM160432
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Molecular mechanism of necroptosis mediated by mixed lineage kinase-like (MLKL) protein - Project Summary/Abstract Necroptosis is a pro-inflammatory form of lytic cell death that plays a critical role in a wide array of human diseases, including cancer, diabetes, inflammatory disorders, neurodegenerative diseases, and infections. Central to this biological process is the Mixed Lineage Kinase Domain-Like protein (MLKL), the terminal executioner of necroptosis, which has become a key molecule for in-depth investigation. It has been known that the N-terminal executioner domain of MLKL is responsible for mediating necroptotic cell death, and the C- terminal pseudokinase domain regulates its activation through phosphorylation by upstream kinase RIPK3. Despite numerous MLKL structures being determined in recent years, the precise molecular mechanism by which MLKL executes necroptosis remains poorly understood. This study aims to provide a comprehensive understanding of the structure-activity relationship of MLKL, which could significantly accelerate the development of targeted therapies in the field. We will begin by focusing on the recently identified MLKL-like protein, NS3, in norovirus. Based on the cryo-EM structure of a ring formed by the NS3 MLKL-like executioner domain we have recently determined, we will analyze the molecular mechanisms of its assembly, lipid-binding, and membrane insertion during viral infection-induced necroptotic cell death. In parallel, we will directly investigate human MLKL to dissect the mechanism of membrane rupture in necroptosis. We propose to determine the structures of human MLKL in multiple functional states, ranging from its inactive form to its active assemblies, offering detailed insights into its molecular dynamics. Lastly, we will extend our research to MLKL-like proteins in bacteria. We have identified several bacterial MLKL-like proteins and validated their membrane permeabilization activities in vitro. Further structural and functional studies on these bacterial MLKLs will uncover both conserved and unique features within the MLKL superfamily, deepening our understanding of necroptosis and the evolutionary trajectory of MLKL-mediated cell death.


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: 2026 ( Subtotal = $429,072 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Biomedical Research and Research Training	000	1	8/26/2026	NEW	$429,072
														Subtotal = $429,072

Grand Total All Awards = $429,072

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Molecular mechanism of necroptosis mediated by mixed lineage kinase-like (MLKL) protein

Award Number: R01GM160432

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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