Molecular determinants of phospholipid synergy in blood clotting

Narjes Tavoosi, Rebecca L. Davis-Harrison, Taras V. Pogorelov, Y. Zenmei Ohkubo, Mark J. Arcario, Mary C. Clay, Chad M. Rienstra, Emad Tajkhorshid, James H. Morrissey

Research output: Contribution to journalArticle

Abstract

Many regulatory processes in biology involve reversible association of proteins with membranes. Clotting proteins bind to phosphatidylserine (PS) on cell surfaces, but a clear picture of this interaction has yet to emerge. We present a novel explanation for membrane binding by GLA domains of clotting proteins, supported by biochemical studies, solid-state NMR analyses, and molecular dynamics simulations. The model invokes a single "phospho-L- serine-specific" interaction and multiple "phosphate-specific" interactions. In the latter, the phosphates in phospholipids interact with tightly bound Ca2+ in GLA domains. We show that phospholipids with any headgroup other than choline strongly synergize with PS to enhance factor X activation. We propose that phosphatidylcholine and sphingomyelin (the major external phospholipids of healthy cells) are anticoagulant primarily because their bulky choline headgroups sterically hinder access to their phosphates. Following cell damage or activation, exposed PS and phosphatidylethanolamine collaborate to bind GLA domains by providing phospho-L-serine-specific and phosphate-specific interactions, respectively.

Original languageEnglish (US)
Pages (from-to)23247-23253
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number26
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Molecular determinants of phospholipid synergy in blood clotting'. Together they form a unique fingerprint.

  • Cite this

    Tavoosi, N., Davis-Harrison, R. L., Pogorelov, T. V., Ohkubo, Y. Z., Arcario, M. J., Clay, M. C., Rienstra, C. M., Tajkhorshid, E., & Morrissey, J. H. (2011). Molecular determinants of phospholipid synergy in blood clotting. Journal of Biological Chemistry, 286(26), 23247-23253. https://doi.org/10.1074/jbc.M111.251769