Faculty Collaboration Database

Structural basis for PECAM-1 homophilic binding. Blood 2016 Feb 25;127(8):1052-61

Date

12/25/2015

Pubmed ID

26702061

Pubmed Central ID

PMC4768429

DOI

10.1182/blood-2015-07-660092

Scopus ID

2-s2.0-84960356253 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa member of the immunoglobulin gene superfamily (IgSF) that is present on the surface of circulating platelets and leukocytes, and highly expressed at the junctions of confluent endothelial cell monolayers. PECAM-1-mediated homophilic interactions, known to be mediated by its 2 amino-terminal immunoglobulin homology domains, are essential for concentrating PECAM-1 at endothelial cell intercellular junctions, where it functions to facilitate diapedesis, maintain vascular integrity, and transmit survival signals into the cell. Given the importance of PECAM-1-mediated homophilic interactions in mediating each of these cell physiological events, and to reveal the nature and orientation of the PECAM-1-PECAM-1 homophilic-binding interface, we undertook studies aimed at determining the crystal structure of the PECAM-1 homophilic-binding domain, which is composed of amino-terminal immunoglobulin homology domains 1 and 2 (IgD1 and IgD2). The crystal structure revealed that both IgD1 and IgD2 exhibit a classical IgSF fold, having a β-sandwich topology formed by 2 sheets of antiparallel β strands stabilized by the hallmark disulfide bond between the B and F strands. Interestingly, despite previous assignment to the C2 class of immunoglobulin-like domains, the structure of IgD1 reveals that it actually belongs to the I2 set of IgSF folds. Both IgD1 and IgD2 participate importantly in the formation of the trans homophilic-binding interface, with a total buried interface area of >2300 Å(2). These and other unique structural features of PECAM-1 allow for the development of an atomic-level model of the interactions that PECAM-1 forms during assembly of endothelial cell intercellular junctions.

Author List

Paddock C, Zhou D, Lertkiatmongkol P, Newman PJ, Zhu J

Authors

Peter J. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Jieqing Zhu PhD Assistant Professor, Associate Investigator in the Biochemistry department at BloodCenter of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Cell Adhesion
Crystallography, X-Ray
Electrophoresis, Polyacrylamide Gel
Endothelial Cells
Humans
Intercellular Junctions
Mice
Models, Molecular
Molecular Sequence Data
Platelet Endothelial Cell Adhesion Molecule-1
Protein Binding
Protein Structure, Tertiary
Species Specificity
Transfection