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Dimerization of LT?R by LT?1?2 is necessary and sufficient for signal transduction.


ABSTRACT: Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)?1?2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LT?1?2 trigger signaling via LT? Receptor (LT?R) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LT?1?2 possesses two binding sites for LT?R with distinct affinities and that dimerization of LT?R by LT?1?2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LT?1?2, LT?R, and the fab fragment of an antibody that blocks LT?R activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LT?1?2 reveal the high-affinity site. NF-?B reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LT?R.

SUBMITTER: Sudhamsu J 

PROVIDER: S-EPMC3856818 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction.

Sudhamsu Jawahar J   Yin Jianping J   Chiang Eugene Y EY   Starovasnik Melissa A MA   Grogan Jane L JL   Hymowitz Sarah G SG  

Proceedings of the National Academy of Sciences of the United States of America 20131118 49


Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTα1β2 trigger signaling via LTβ Receptor (LTβR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTα1β2 possesses two binding sites for LTβR with distinct affinities and that dimerizati  ...[more]

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