Dimerization Of Lt Beta R By Lt Alpha(1)Beta(2) Is Necessary And Sufficient For Signal Transduction
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(2013)
Abstract
Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT) alpha(1)beta(2) is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LT alpha(1)beta(2) trigger signaling via LT beta Receptor (LT beta R) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LT alpha(1)beta(2) possesses two binding sites for LT beta R with distinct affinities and that dimerization of LT beta R by LT alpha(1)beta(2) is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LT alpha(1)beta(2), LT beta R, and the fab fragment of an antibody that blocks LT alpha R activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LT alpha(1)beta(2) reveal the high-affinity site. NF-kappa B reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LT beta R.
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Key words
crystallography, cytokines, mechanism, biophysics
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