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bioRxiv · 10.1101/2020.07.10.196980

The Amyloid Structure of Mouse RIPK3 (Receptor Interacting Protein Kinase 3) in Cell Necroptosis

Xialian Wu·Hong Hu·Xingqi Dong·Jing Zhang·Jian Wang·Charles Schwieters·Jing Liu·Guo xiang Wu·Bing Li·Jing yu Lin·Huayi Wang·Junxia Lu
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Abstract

RIPK3 amyloid complex plays crucial roles in execution of TNF-induced necroptosis and in response to immune defense in both human and mouse. We have structurally characterized the mouse RIPK3 homogeneous self-assembly using solid-state NMR, illustrating a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register {beta}-sheets. The structure is different from previously published human RIPK1/RIPK3 hetero-amyloid complex. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for RIPK3-mediated necroptosis. The structural integrity of RIPK3 fibril with three {beta}-strands is necessary for the signaling. Molecular dynamics simulation of the mouse RIPK1/RIPK3 model indicates less stable for the hetero-amyloid to adopt RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation is revealed for the first time, providing a missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.

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Xialian Wu, Hong Hu, Xingqi Dong, Jing Zhang, Jian Wang, Charles Schwieters, Jing Liu, Guo xiang Wu, Bing Li, Jing yu Lin, Huayi Wang, Junxia Lu. 2020-07-11. The Amyloid Structure of Mouse RIPK3 (Receptor Interacting Protein Kinase 3) in Cell Necroptosis. https://doi.org/10.1101/2020.07.10.196980

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