Structural determinants of herpesvirus entry mediator recognition by murine B and T lymphocyte attenuator

Christopher A. Nelson, Marcel D. Fremont, John R. Sedy, Paula S. Norris, Carl F. Ware, Kenneth M. Murphy, Daved H. Fremont

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

The B and T lymphocyte attenuator (BTLA) appears to act as a negative regulator of T cell activation and growth. BTLA specifically interacts with herpesvirus entry mediator (HVEM), a member of the TNFR family. Herein, we have undertaken surface plasmon resonance studies to quantitatively assess BTLA and HVEM ectodomain interactions. We find that soluble BALB/cJ BTLA engages HVEM with an equilibrium affinity of 0.97 ± 0.19 μM while the C57BL/6 BTLA binds slightly better with an equilibrium affinity of 0.42 ± 0.06 μM. Despite its lower affinity for HVEM, the kinetic half-life of BALB/cJ BTLA complexes are twice as long as observed for C57BL/6 BTLA (4 vs 2 s). To further explore these interactions, we solved the crystal structure of a murine BTLA (BALB/cJ) ectodomain at 1.8-Å resolution, revealing a β sandwich fold with strong similarity to I-set members of the Ig superfamily. Using a structure-based mutagenesis strategy, we then examined the individual contributions of 26 BTLA surface-exposed residues toward HVEM binding. Four single-site substitutions were identified that decrease HVEM binding below detectable levels and two that decrease binding by more than half. All six of these cluster at the edge of the β sandwich in a membrane distal patch formed primarily from the A and G strands. This patch falls within the contacting surface recently revealed in the crystal structure of the human BTLA-HVEM cocomplex. The critical binding residues identified here are highly conserved across species, suggesting that BTLA employs a conserved binding mode for HVEM recognition.

Original languageEnglish
Pages (from-to)940-947
Number of pages8
JournalJournal of Immunology
Volume180
Issue number2
DOIs
StatePublished - Jan 15 2008

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