Structural studies on human PECAM-1 trans-homophilic dimerization revealing cell adhesion mechanism

Abstract

Platelet/Endothelial Cell Adhesion Molecule-1, abbreviated to PECAM-1 and also known as CD31, is a member of cell adhesion molecules. It participates in cell adhesion by affecting endothelium integrity and leukocyte transmigration, immunological reaction by regulating tolerance of immune cells and pathogenesis of vascular diseases. The signaling transduction through PECAM-1 from outside to inside of cell is associated with either homophilic or heterophilic binding patterns of PECAM-1. Both of the interactions result from the extracellular region containing six immunoglobulin-like (IgL) domains for signal induction and cytoplasmic tail with immune-receptor tyrosine-based inhibitory motifs for initiating downstream signal pathway in cell. However, the detailed mechanism of trans-homophilic binding pattern of human PECAM-1 is still unknown. Here, in this project, I resolved the crystal structure of non-glycosylated IgL1-2 by using X-ray crystallography. Either IgL1 or IgL2 possesses classical immunoglobulin architecture with two beta-sheet layers anchored by one disulfide bond. Each layer is composed of 3-6 parallel beta-strands. The dimerization of IgL1-2 due to both hydrophilic and hydrophobic interactions is verified by small angle X-ray scattering method in solution. Cell adhesion assay based on mutagenesis further proves the trans-homophilic dimerization of human PECAM-1. Our structure provides insights into understanding the multiple functions of PECAM-1 in endothelium integrity, immune response, and diapedesis.