The amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis

Xia-lian Wu, Hong Hu, Xing-qi Dong, Jing Zhang, Jian Wang, Charles D. Schwieters, Jing Liu, Guo-xiang Wu, Bing Li, Jing-yu Lin, Hua-yi Wang () and Jun-xia Lu ()
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Xia-lian Wu: ShanghaiTech University
Hong Hu: ShanghaiTech University
Xing-qi Dong: ShanghaiTech University
Jing Zhang: ShanghaiTech University
Jian Wang: ShanghaiTech University
Charles D. Schwieters: National Institutes of Health
Jing Liu: ShanghaiTech University
Guo-xiang Wu: ShanghaiTech University
Bing Li: ShanghaiTech University
Jing-yu Lin: ShanghaiTech University
Hua-yi Wang: ShanghaiTech University
Jun-xia Lu: ShanghaiTech University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract RIPK3 amyloid complex plays crucial roles during TNF-induced necroptosis and in response to immune defense in both human and mouse. Here, we have structurally characterized mouse RIPK3 homogeneous self-assembly using solid-state NMR, revealing a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. This structure differs from previously published human RIPK1/RIPK3 hetero-amyloid complex structure, which adopted a serpentine fold. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for TNF-induced necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for signaling. Molecular dynamics simulations with a mouse RIPK1/RIPK3 model indicate that the hetero-amyloid is less stable when adopting the RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation would provide the missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.

Date: 2021
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DOI: 10.1038/s41467-021-21881-2

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