Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 14, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022933118
Keywords
necroptosis; amyloid fibril; Cryo-EM; ssNMR
Categories
Funding
- Analytical Instrumentation Center [SPST-AIC 10112914]
- School of Physical Science and Technology at ShanghaiTech University
- Major State Basic Research Development Program [2016YFA0501902, 2017YFA0504804]
- National Natural Science Foundation (NSF) of China [91853113, 31872716, 31770790]
- Science and Technology Commission of Shanghai Municipality [18JC1420500]
- Eastern Scholar project - Shanghai Municipal Education Commission
- Shanghai Municipal Science and Technology Major Project [2019SHZDZX02]
- Shanghai Science and Technology Committee [20XD1425000]
- Yangfan program of the Shanghai municipal government [19YF1433500]
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RIPK3, a key protein involved in necroptosis, forms amyloid fibrils via its RHIM domain. The study determined the fibril structure of RIPK3 C-terminal domain containing RHIM using cryo-EM and solid-state NMR. The unique assembly of RIPK3-CTD fibril may contribute to efficient phosphorylation of RIPK3 kinase domain.
Receptor-interacting protein kinases 3 (RIPK3), a central node in necroptosis, polymerizes in response to the upstream signals and then activates its downstream mediator to induce cell death. The active polymeric form of RIPK3 has been indicated as the form of amyloid fibrils assembled via its RIP homotypic interaction motif (RHIM). In this study, we combine cryogenic electron microscopy and solid-state NMR to determine the amyloid fibril structure of RIPK3 RHIM-containing C-terminal domain (CTD). The structure reveals a single protofilament composed of the RHIM domain. RHIM forms three beta-strands (referred to as strands 1 through 3) folding into an S shape, a distinct fold from that in complex with RIPK1. The consensus tetrapeptide VQVG of RHIM forms strand 2, which zips up strands 1 and 3 via heterozipper-like interfaces. Notably, the RIPK3-CTD fibril, as a physiological fibril, exhibits distinctive assembly compared with pathological fibrils. It has an exceptionally small fibril core and twists in both handedness with the smallest pitch known so far. These traits may contribute to a favorable spatial arrangement of RIPK3 kinase domain for efficient phosphorylation.
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