Lactadherin’s Multistate Binding Predicts Stable Membrane-Bound Conformations of Factors V and VIII’s C Domains

Kevin J. Cheng, Ashley M. De Lio, Riya Jain, Divyani Paul, James H. Morrissey, Taras V. Pogorelov

Research output: Contribution to journalArticlepeer-review

Abstract

Protein binding to negatively charged lipids is essential for maintaining numerous vital cellular processes where its dysfunction can lead to various diseases. One such protein that plays a crucial role in this process is lactadherin, which competes with coagulation factors for membrane binding sites to regulate blood clotting. Despite identifying key binding regions of these proteins through structural and biochemical studies, models incorporating membrane dynamics are still lacking. In this study, we report on the multimodal binding of lactadherin and use it to gain insight into the binding mechanisms of its C domain homologs, factor V and factor VIII. Molecular dynamics simulations enhanced with the highly mobile mimetic model enabled the determination of lactadherin’s multimodal binding on membranes that revealed critical interacting residues consistent with prior NMR and mutagenesis data. The binding occurred primarily via two dynamic structural ensembles: an inserted state and an unreported, highly conserved side-lying state driven by a cationic patch. We utilized these findings to analyze the membrane binding domains of coagulation factors V and VIII and identified their preferred membrane-bound conformations. Specifically, factor V’s C domains maintained an inserted state, while factor VIII preferred a tilted, side-lying state that permitted antibody binding. Insight into lactadherin’s atomistically resolved membrane interactions from a multistate perspective can guide new therapeutic opportunities in treating diseases related to blood coagulation.

Original languageEnglish (US)
Pages (from-to)3020-3032
Number of pages13
JournalBiochemistry
Volume62
Issue number20
DOIs
StatePublished - Oct 17 2023

ASJC Scopus subject areas

  • Biochemistry

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