8YM6

Structure of Caspase-8/cFLIP death effector domain assembly

Summary for 8YM6

• Entry DOI: 10.2210/pdb8ym6/pdb
• Descriptor: Caspase-8 subunit p10, CASP8 and FADD-like apoptosis regulator subunit p43 (2 entities in total)
• Functional Keywords: fadd, caspase-8, cflip, death effector domain, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 13
• Total formula weight: 278492.60

Authors

Lin, S.-C.,Yang, C.-Y. (deposition date: 2024-03-08, release date: 2024-10-30)

Primary citation

Yang, C.Y.,Tseng, Y.C.,Tu, Y.F.,Kuo, B.J.,Hsu, L.C.,Lien, C.I.,Lin, Y.S.,Wang, Y.T.,Lu, Y.C.,Su, T.W.,Lo, Y.C.,Lin, S.C.
Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
Nat Commun, 15:8974-8974, 2024

PubMed 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.

PubMed: 39419969
DOI: 10.1038/s41467-024-53306-1

Experimental method

X-RAY DIFFRACTION (3.3 Å)