Abstract
Cell adhesion involved in signal transduction, tissue integrity and pathogen infection is mainly mediated by cell adhesion molecules (CAM). One CAM member, platelet–endothelial-cell adhesion molecule-1 (PECAM-1), plays an important role in tight junction among endothelia cells, leukocyte trafficking, and immune response through its homophilic and heterophilic binding patterns. Both kinds of interactions, which lead to endogenous and exogenous signal transmission, are derived from extracellular immunoglobulin-like (IgL) domains and cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of PECAM-1. To date, the mechanism of trans-homophilic interaction of PECAM-1 remains unclear. Here, we present the crystal structure of PECAM-1 IgL1-2 trans-homo dimer. Both IgL 1 and 2 adopt the classical Ig domain conformation comprised of two layers of β-sheets possessing antiparallel β-strands with each being anchored by a pair of cysteines forming a disulfide bond. The dimer interface includes hydrophobic and hydrophilic interactions. The Small-Angle X-ray Scattering (SAXS) envelope of PECAM-1 IgL1-6 supported such a dimer formation in solution. Cell adhesion assays on wildtype and mutant PECAM-1 further characterized the structural determinants in cell junction and communication.
Highlights
Platelet–endothelial-cell adhesion molecule-1 (PECAM-1), well known as CD31, is a 130 kilodalton protein which belongs to both type I transmembrane glycoprotein and immunoglobulin (Ig) superfamily[1]
The extracellular portions of platelet–endothelial-cell adhesion molecule-1 (PECAM-1) on adjacent cell surfaces show a homophilic binding pattern, which contributes to tight cell junction and builds a barrier between basal lamina and blood vessel together with other cell adhesion molecules[12,13]
PECAM-1 participates in the formation of a strong barrier with other adhesion molecules between blood vessel and basal lamina
Summary
Platelet–endothelial-cell adhesion molecule-1 (PECAM-1), well known as CD31, is a 130 kilodalton protein which belongs to both type I transmembrane glycoprotein and immunoglobulin (Ig) superfamily[1]. PECAM-1 interacts with homogeneous molecules in a trans-homophilic binding manner that does not rely on transmembrane and cytoplasmic regions. Numerous important physiological functions of PECAM-1 root in homophilic and heterophilic interactions on its extracellular six IgL domains, little molecular mechanism is known except the recent reported IgL1–2 structure by Zhu and co-workers[26]. This structure was a cis-dimer in one asymmetric unit with the IgL2 “fold-out” as opposed to classical immunoglobulin. We report a crystal structure of trans-homophilic IgL1-2 dimer to reveal the binding pattern of the IgL1-2 homo-interactions and to provide mechanistic understanding of IgL1-2 in cell adhesion
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