title: Molecular determinants of phospholipid synergy in blood clotting.
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 Ca(2+) 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.
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Narjes
authors.initials: N
authors.lastname: Tavoosi
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Davis-Harrison
authors.forename: Taras V
authors.initials: TV
authors.lastname: Pogorelov
authors.forename: Y Zenmei
authors.initials: YZ
authors.lastname: Ohkubo
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Arcario
authors.forename: Mary C
authors.initials: MC
authors.lastname: Clay
authors.forename: Chad M
authors.initials: CM
authors.lastname: Rienstra
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
authors.forename: James H
authors.initials: JH
authors.lastname: Morrissey
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D005170:Factor X / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D005170:Factor X; D002118:Calcium