Modeling the molecular fingerprint of protein-lipid interactions of MLKL on complex bilayers.

Autor:	Ramirez RX; Department of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United States., Campbell O; Department of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United States., Pradhan AJ; Department of Chemistry, College of Arts and Sciences, University at Buffalo, Buffalo, NY, United States., Atilla-Gokcumen GE; Department of Chemistry, College of Arts and Sciences, University at Buffalo, Buffalo, NY, United States., Monje-Galvan V; Department of Chemical and Biological Engineering, School of Engineering and Applied Sciences, University at Buffalo, Buffalo, NY, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in chemistry [Front Chem] 2023 Jan 12; Vol. 10, pp. 1088058. Date of Electronic Publication: 2023 Jan 12 (Print Publication: 2022).
DOI:	10.3389/fchem.2022.1088058
Abstrakt:	Lipids, the structural part of membranes, play important roles in biological functions. However, our understanding of their implication in key cellular processes such as cell division and protein-lipid interaction is just emerging. This is the case for molecular interactions in mechanisms of cell death, where the role of lipids for protein localization and subsequent membrane permeabilization is key. For example, during the last stage of necroptosis, the mixed lineage kinase domain-like (MLKL) protein translocates and, eventually, permeabilizes the plasma membrane (PM). This process results in the leakage of cellular content, inducing an inflammatory response in the microenvironment that is conducive to oncogenesis and metastasis, among other pathologies that exhibit inflammatory activity. This work presents insights from long all-atom molecular dynamics (MD) simulations of complex membrane models for the PM of mammalian cells with an MLKL protein monomer. Our results show that the binding of the protein is initially driven by the electrostatic interactions of positively charged residues. The protein bound conformation modulates lipid recruitment to the binding site, which changes the local lipid environment recruiting PIP lipids and cholesterol, generating a unique fingerprint. These results increase our knowledge of protein-lipid interactions at the membrane interface in the context of molecular mechanisms of the necroptotic pathway, currently under investigation as a potential treatment target in cancer and inflamatory diseases. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Ramirez, Campbell, Pradhan, Atilla-Gokcumen and Monje-Galvan.)
Databáze:	MEDLINE
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