8YBX

Structure of the FADD/Caspase-8/cFLIP death effector domain assembly

Summary for 8YBX

• Entry DOI: 10.2210/pdb8ybx/pdb
• EMDB information: 39126
• Descriptor: Caspase-8 subunit p10, CASP8 and FADD-like apoptosis regulator subunit p43, FAS-associated death domain protein (3 entities in total)
• Functional Keywords: fadd, caspase-8, cellular flice-like inhibitory protein, death effector domain, apoptosis
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 322233.46

Authors

Lin, S.-C.,Yang, C.-Y. (deposition date: 2024-02-16, release date: 2024-05-15)

Primary citation

Yang, C.Y.,Lien, C.I.,Tseng, Y.C.,Tu, Y.F.,Kulczyk, A.W.,Lu, Y.C.,Wang, Y.T.,Su, T.W.,Hsu, L.C.,Lo, Y.C.,Lin, S.C.
Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis.
Nat Commun, 15:3791-3791, 2024

PubMed Abstract: Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.

PubMed: 38710704
DOI: 10.1038/s41467-024-47990-2

Experimental method

ELECTRON MICROSCOPY (3.68 Å)