Mechanism of procaspase-8 activation by c-FLIPL

Proc Natl Acad Sci U S A. 2009 May 19;106(20):8169-74. doi: 10.1073/pnas.0812453106. Epub 2009 May 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / chemistry
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Caspase 8 / chemistry
  • Caspase 8 / metabolism*
  • Crystallography, X-Ray
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Humans
  • Protein Conformation
  • Protein Multimerization


  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Enzyme Precursors
  • Caspase 8

Associated data

  • PDB/3H11
  • PDB/3H13