Title: Lipid-Dependent Assembly and Budding of SARS-CoV-2

By:  Dr. Robert V. Stahelin

Retter Professor of Pharmacy

Professor of Medicinal Chemistry and Molecular Pharmacology, Purdue University, Indiana

Abstract:

M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, Mshort and Mlong, and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes Mshort. Cryo-EM structures show C1P specifically binds Mshort at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting Mshort-C1P interaction alters M subcellular localization, reduces colocalization with Spike and E, and impairs subsequent virus-like particle cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which Mshort is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.

Bio:

Prof. Dr. Robert V. Stahelin is the Retter Professor of Pharmacy and a Professor of Medicinal Chemistry and Molecular Pharmacology at Purdue University, West Lafayette, IN, USA. Since receiving his Ph.D. in Chemistry in 2003 from the University of Illinois at Chicago, he has specialized in biological membranes, sphingolipids signaling in cancers, and lipid-binding proteins. His current research is targeted at understanding how viral proteins interact with host cell lipids to hijack host cell membranes for the formation of the viral lipid envelope. The goals of his current research are to identify protein drug targets in the viral life cycle, understanding the structural and biophysical basis of viral assembly and budding, and understanding their biological mechanisms by which viruses alter host lipid metabolism. He has published more than 150 PubMed/SCIE-listed papers on lipids, and his research has been frequently highlighted by prominent media outlets.

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