The crystal structure of the endothelial protein C receptor and a bound phospholipid.
The endothelial cell protein C receptor (EPCR) shares approximately 20% sequence identity with the major histocompatibility complex class 1/CD1 family of molecules, accelerates the thrombin-thrombomodulin-dependent generation of activated protein C, a natural anticoagulant, binds to activated neutrophils, and can undergo translocation from the plasma membrane to the nucleus. Blocking protein C/activated protein C binding to the receptor inhibits not only protein C activation but the ability of the host to respond appropriately to bacterial challenge, exacerbating both the coagulant and inflammatory responses. To understand how EPCR accomplishes these multiple tasks, we solved the crystal structure of EPCR alone and in complex with the phospholipid binding domain of protein C. The structures were strikingly similar to CD1d. A tightly bound phospholipid resides in the groove typically involved in antigen presentation. The protein C binding site is outside this conserved groove and is distal from the membrane-spanning domain. Extraction of the lipid resulted in loss of protein C binding, which could be restored by lipid reconstitution. CD1d augments the immune response by presenting glycolipid antigens. The EPCR structure is a model for how CD1d binds lipids and further suggests additional potential functions for EPCR in immune regulation, possibly including the anti-phospholipid syndrome.
Oganesyan
Vaheh
V
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.
Oganesyan
Natalia
N
Terzyan
Simon
S
Qu
Dongfeng
D
Dauter
Zbigniew
Z
Esmon
Naomi L
NL
Esmon
Charles T
CT
D000818:Animals; D001779:Blood Coagulation Factors; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D016296:Mutagenesis; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D001779:Blood Coagulation Factors; D010743:Phospholipids; D011486:Protein C; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C091963:activated protein C receptor