LFA-1 binding destabilizes the JAM-A homophilic interaction during leukocyte transmigration

Ewa P. Wojcikiewicz, Rory R. Koenen, Line Fraemohs, Julia Minkiewicz, Hashem Azad, Christian Weber, Vincent T. Moy

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Leukocyte transendothelial migration into inflamed areas is regulated by the integrity of endothelial cell junctions and is stabilized by adhesion molecules including junctional adhesion molecule-A (JAM-A). JAM-A has been shown to participate in homophilic interactions with itself and in heterophilic interactions with leukocyte function-associated antigen-1 (LFA-1) via its first and second immunoglobulin domains, respectively. Using competitive binding assays in conjunction with atomic force microscopy adhesion measurements, we provide compelling evidence that the second domain of JAM-A stabilizes the homo-philic interaction because its deletion suppresses the dynamic strength of the JAM-A homophilic interaction. Moreover, binding of the LFA-1 inserted domain to the second domain of JAM-A reduces the dynamic strength of the JAM-A homophilic interaction to the level measured with the JAM-A domain 2 deletion mutant. This finding suggests that LFA-1 binding cancels the stabilizing effects of the second immunoglobulin domain of JAM-A. Finally, our atomic force microscopy measurements reveal that the interaction of JAM-A with LFA-1 is stronger than the JAM-A homophilic interaction. Taken together, these results suggest that LFA-1 binding to JAM-A destabilizes the JAM-A homophilic interaction. In turn, the greater strength of the LFA-1/JAM-A complex permits it to support the tension needed to disrupt the JAM-A homophilic interaction, thus allowing transendothelial migration to proceed.

Original languageEnglish (US)
Pages (from-to)285-293
Number of pages9
JournalBiophysical journal
Volume96
Issue number1
DOIs
StatePublished - Jan 7 2009

ASJC Scopus subject areas

  • Biophysics

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