sPLA2-V inhibits EPCR anticoagulant and antiapoptotic properties by accommodating lysophosphatidylcholine or PAF in the hydrophobic groove

Abstract

The endothelial protein C receptor (EPCR) plays an important role in cardiovascular disease by binding protein C/activated protein C (APC). EPCR structure contains a hydrophobic groove filled with an unknown phospholipid needed to perform its function. It has not been established whether lipid exchange takes place in EPCR as a regulatory mechanism of its activity. Our objective was to identify this phospholipid and to explore the possibility of lipid exchange as a regulatory mechanism of EPCR activity driven by the endothelially expressed secretory group V phospholipase A 2 (sPLA 2 -V). We identified phosphatidylcholine (PCh) as the major phospholipid bound to human soluble EPCR (sEPCR). PCh in EPCR could be exchanged for lysophosphatidylcholine (

Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

“…3 Recent studies showed phosphatidylcholine as the major phospholipid bound to human EPCR, which could be exchanged with lysophosphatidylcholine and platelet activating factor, facilitated by the enzymatic action of secretory group V phospholipase A2. 4 The placement of lysophosphatidylcholine and platelet activating factor in the hydrophobic groove impaired the ability of EPCR to bind protein C. 4 The crystal structure of the complex of human EPCR bound to the human protein C Gla domain identified that Phe-4 and Leu-8 located in the conserved v-loop of the protein C Gla domain contribute to the majority of the binding energy required to interact with EPCR. Another 3 residues of the protein C Gla domain that interact with EPCR are Gla-7, Gla-27, and Gla-29.…”

Activated protein C: biased for translation

“…This latter point became evident from the switch in thrombin's functional selectivity from endothelial-barrier disruptive to barrier protective on "EPCR occupancy," discovered by Rezaie. 8,89 Not surprisingly, the impairment of cellular EPCR function and associated acquired functional deficiency of the protein C system due to EPCR encryption via editing of the EPCR-embedded lipid 90,91 or due to EPCR targeting by Plasmodium falciparum-infected erythrocytes in severe and cerebral malaria [92][93] underline the integral role of EPCR for the protein C system. 7,94,95 Temporal regulation and spatial organization of the PAR interactome…”

Plasmodium falciparum picks (on) EPCR

“…7 Furthermore, TNF-a-mediated phospholipase A2 (sPLA2) secretion from leukocytes and possibly brain ECs may contribute to EPCR encryption and loss of its APC-binding function that results from sPLA2-mediated modification to phospholipid embedded in EPCR while potentially leaving interactions with IEs relatively unaffected. 21 The findings by Moxon et al are supported by previous studies in which protein C-null mice or mice carrying FVL demonstrate selective fibrin deposition in brain blood vessels. 22,23 These results contrast with those of antithrombin III-null mice, which form fibrin deposits in the heart and liver but not the brain.…”