Functional amyloids are poorly understood while they are considered to be playing indispensable roles in biological systems. Here, we studied Receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) which mediate tumor necrosis factor (TNF)-induced cell-fate regulation. Depending on cellular context, RIPK1 and RIPK3 can form a hetero-amyloid through their RIP homotypic interaction motifs (RHIMs) with consensus sequences IQIG (RIPK1) and VQVG (RIPK3) to initiate a unique death pathway, known as necroptosis. Our group has solved the core structure of the complex-RIPK1/RIPK3 by solid-state NMR; it’s shown that RIPK1 and RIPK3 alternately to form heterotypic β sheets with two such β sheets binding together along a compact hydrophobic interface. This was the first detailed structure of a hetero-amyloid, which could potentially elucidate the structural basis of signal transduction in necroptosis.<br/>We’re also studying a viral protein- murine cytomegalovirus protein M45 that protects cells from necroptosis induced by TNFR activation. The N-terminal 90 residues of the M45 protein, which contain a RHIM domain, have been shown to sufficiently confer protection against TNFR-induced necroptosis. The Sunde group has shown that this N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils and interacts with the RHIMs of RIPK1 and RIPK3 to form hetero-amyloid fibrils in vitro. The M45 RHIM is also believed to preferentially interact with RIPK3 over RIPK1 and alter the properties of the host RHIM protein assemblies, which may explain its ability to inhibit necroptosis. Solving the structure of M45-RIPK3 complex is essential to uncover the underlying mechanism.<br/>

Structural studies of hetero-amyloid signaling complexes using solid-state NMR

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.