3H13

c-FLIPL protease-like domain

Summary for 3H13

• Entry DOI: 10.2210/pdb3h13/pdb
• Related: 3H11
• Descriptor: CASP8 and FADD-like apoptosis regulator (2 entities in total)
• Functional Keywords: cflip-l, dimer, cell death, alternative splicing, apoptosis, host-virus interaction, polymorphism
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31450.22

Authors

Jeffrey, P.D.,Yu, J.W.,Shi, Y. (deposition date: 2009-04-10, release date: 2009-04-28, Last modification date: 2024-02-21)

Primary citation

Yu, J.W.,Jeffrey, P.D.,Shi, Y.
Mechanism of procaspase-8 activation by c-FLIPL.
Proc.Natl.Acad.Sci.USA, 106:8169-8174, 2009

PubMed Abstract: Cellular FLICE-inhibitory protein (c-FLIP(L)) is a key regulator of the extrinsic cell death pathway. Although widely regarded as an inhibitor of initiator caspase activation and cell death, c-FLIP(L) is also capable of enhancing procaspase-8 activation through heterodimerization of their respective protease domains. However, the underlying mechanism of this activation process remains enigmatic. Here, we demonstrate that cleavage of the intersubunit linker of c-FLIP(L) by procaspase-8 potentiates the activation process by enhancing heterodimerization between the two proteins and vastly improving the proteolytic activity of unprocessed caspase-(C)8. The crystal structures of the protease-like domain of c-FLIP(L) alone and in complex with zymogen C8 identify the unique determinants that favor heterodimerization over procaspase-8 homodimerization, and induce the latent active site of zymogen C8 into a productive conformation. Together, these findings provide molecular insights into a key aspect of c-FLIP(L) function that modulates procaspase-8 activation to elicit diverse responses in different cellular contexts.

PubMed: 19416807
DOI: 10.1073/pnas.0812453106

Experimental method

X-RAY DIFFRACTION (2.2 Å)