4M9X

Crystal structure of CED-4 bound CED-3 fragment

Summary for 4M9X

• Entry DOI: 10.2210/pdb4m9x/pdb
• Related: 4M9S 4M9Y 4M9Z
• Descriptor: Cell death protein 4, CED-3 fragment, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: apoptosome, apoptosis
• Biological source: Caenorhabditis elegans (nematode); More
• Cellular location: Mitochondrion: P30429
• Total number of polymer chains: 4
• Total formula weight: 128789.69

Authors

Huang, W.J.,Jinag, T.Y.,Choi, W.Y.,Wang, J.W.,Shi, Y.G. (deposition date: 2013-08-15, release date: 2013-10-23, Last modification date: 2023-11-08)

Primary citation

Huang, W.,Jiang, T.,Choi, W.,Qi, S.,Pang, Y.,Hu, Q.,Xu, Y.,Gong, X.,Jeffrey, P.D.,Wang, J.,Shi, Y.
Mechanistic insights into CED-4-mediated activation of CED-3.
Genes Dev., 27:2039-2048, 2013

PubMed Abstract: Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4-CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 Å resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4-CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.

PubMed: 24065769
DOI: 10.1101/gad.224428.113

Experimental method

X-RAY DIFFRACTION (3.344 Å)