Structure of the C-terminal domain of TRADD reveals a novel fold in the death domain superfamily.

The TNFR1-associated death domain protein (TRADD) is an intracellular adaptor protein involved in various signaling pathways, such as antiapoptosis. Its C-terminal death domain (DD) is responsible for binding other DD-containing proteins including the p75 neurotrophin receptor (p75^NTR). Here we present a solution structure of TRADD DD derived from high-resolution NMR spectroscopy. The TRADD DD comprises two super-secondary structures, an all-helix Greek key motif and a β-hairpin motif flanked by two α helices, which make it unique among all known DD structures. The β-hairpin motif is essential for TRADD DD to fold into a functional globular domain. The highly-charged surface suggests a critical role of electrostatic interactions in TRADD DD-mediated signaling. This novel structure represents a new class within the DD superfamily and provides a structural basis for studying homotypic DD interactions. NMR titration revealed a direct weak interaction between TRADD DD and p75^NTR DD monomers. A binding site next to the p75^NTR DD homodimerization interface indicates that TRADD DD recruitment to p75^NTR requires separation of the p75^NTR DD homodimer, explaining the mechanism of NGF-dependent activation of p75^NTR-TRADD-mediated antiapoptotic pathway in breast cancer cell.

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