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J. Biol. Chem., Vol. 277, Issue 28, 24851-24854, July 12, 2002
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,,
,§**§§
From the The endothelial cell protein C
receptor (EPCR) shares ~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.
Cardiovascular Biology Research Program,
§ Howard Hughes Medical Institute, and ¶ Department of
Crystallography, Oklahoma Medical Research Foundation, Oklahoma City,
Oklahoma 73104, SAIC/NCI-Frederick, National Institutes
of Health, Frederick, Maryland 21702, and the Departments
of ** Pathology and Biochemistry
and Molecular Biology, University of Oklahoma Health Sciences
Center, Oklahoma City, Oklahoma 73104
The atomic coordinates and the structure factors (code 1L8J and 1LQV) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
§§ An Investigator for the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Inst., Oklahoma Medical Research Foundation, 825 N. E. 13th St., Oklahoma City, OK 73104. Tel.: 405-271-7571; Fax: 405-271-3137; E-mail: Charles-Esmon@omrf.ouhsc.edu.This article has been cited by other articles:
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