Mechanism of procaspase-8 activation by c-FLIPL Export

@article{citeulike:4547480, abstract = {10.1073/pnas.0812453106 Cellular FLICE-inhibitory protein (c-FLIP) 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 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 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 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 function that modulates procaspase-8 activation to elicit diverse responses in different cellular contexts.}, author = {Yu, Jong W. and Jeffrey, Philip D. and Shi, Yigong}, citeulike-article-id = {4547480}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0812453106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/20/8169.short.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/20/8169.short.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19416807}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19416807}, day = {19}, doi = {10.1073/pnas.0812453106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {activation, caspase-8, extrinsic, flipl, pathway, yu09pdf}, month = {May}, number = {20}, pages = {8169--8174}, posted-at = {2009-05-19 23:48:03}, priority = {2}, title = {Mechanism of procaspase-8 activation by c-FLIPL}, url = {http://dx.doi.org/10.1073/pnas.0812453106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:4547480 L3 - citeulike-article-id:4547480 N2 - 10.1073/pnas.0812453106 Cellular FLICE-inhibitory protein (c-FLIP) 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 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 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 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 function that modulates procaspase-8 activation to elicit diverse responses in different cellular contexts. IS - 20 JF - Proceedings of the National Academy of Sciences EP - 8174 TI - Mechanism of procaspase-8 activation by c-FLIPL VL - 106 SP - 8169 KW - activation KW - caspase-8 KW - extrinsic KW - flipl KW - pathway KW - yu09pdf AU - Yu, Jong AU - Jeffrey, Philip AU - Shi, Yigong PY - 2009/05/19/ UR - http://dx.doi.org/10.1073/pnas.0812453106 ER -