Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes
Year: 2024
Type: article
Abstract: cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions. FADD binds Casp-8 and then cFLIP to form the FADD-Casp8-cFLIP complex. The authors found that the DED complex could assemble in reverse order, where cFLIP oligomerizes to bind Casp-8. The resultant complex could bind FADD, generating the cFLIP-Casp-8-FADD complex by a different mechanism.
Source: Nature Communications
Authors: Chao-Yu Yang, Yi-Chun Tseng, Yi-Fan Tu, Bai-Jiun Kuo, Li-Chung Hsu, Chia-I Lien, You-Sheng Lin, Yin-Ting Wang, Yen-Chen Lu, Tsung-Wei Su, Yu-Chih Lo, Su-Chang Lin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1114616057, G1366094358, Structural and Functional Studies on Irak-Containing Complexes in Innate Immunity and Inflammation, G2320730907, G2339596145, G2886423967, G391228335, Structural and Functional Studies of Caspase-10-Containing Programmed-Cell-Death Complexes and Also Their High-Resolution Single-Particle Cryo-Electron Microscopic Investigations, Structural and Functional Studies of Caspase-10-Containing Programmed-Cell-Death Complexes and Also Their High-Resolution Single-Particle Cryo-Em Investigations ( III ), G5145723220, G6211189553, G640802405, G7081244253, Structural and Functional Studies of the Signaling Complex Assembly between A20, Abin1, and Linear Ubiquitin Chains in Tnfr Signaling Pathway, Structural and Functional Studies of Caspase-10-Containing Cell Death Complexes and Their Electron Micrographic Investigations, G8412288280, Cryo-Em, Biochemical and Biophysical Studies of the Complex Formation Mechanisms via a Human Viral Flip Protein Mc159 in Regulating the Death Receptor-Mediated Signaling
OpenAlex ID: W4403509276