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 journalArticle

41 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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    Wojcikiewicz, E. P., Koenen, R. R., Fraemohs, L., Minkiewicz, J., Azad, H., Weber, C., & Moy, V. T. (2009). LFA-1 binding destabilizes the JAM-A homophilic interaction during leukocyte transmigration. Biophysical journal, 96(1), 285-293. https://doi.org/10.1529/biophysj.108.135491