title: The central role of initiator caspase-9 in apoptosis signal transduction and the regulation of its activation and activity on the apoptosome.
abstract: Key structural and catalytic features are conserved across the entire family of cysteine-dependent aspartate-specific proteases (caspases). Of the caspases involved in apoptosis signal transduction, the initiator caspases-2, -8 and -9 are activated at multi-protein activation platforms, and activation is thought to involve homo-dimerisation of the monomeric zymogens. Caspase-9, the essential initiator caspase required for apoptosis signalling through the mitochondrial pathway, is activated on the apoptosome complex, and failure to activate caspase-9 has profound pathophysiological consequences. Here, we review the pertinent literature on which the currently prevalent understanding of caspase-9 activation is based, extend this view by insight obtained from recent structural and kinetic studies on caspase-9 signalling, and describe an emerging model for the regulation of caspase-9 activation and activity that arise from the complexity of multi-protein interactions at the apoptosome. This integrated view allows us to postulate and to discuss functional consequences for caspase-9 activation and apoptosis execution that may take centre stage in future experimental cell research on apoptosis signalling.
authors.affiliation: Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Maximilian L
authors.initials: ML
authors.lastname: Würstle
authors.forename: Maike A
authors.initials: MA
authors.lastname: Laussmann
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
mesh_terms: D000818:Animals; D017209:Apoptosis; D053478:Apoptosomes; D053453:Caspase 9 / Q000502:physiology*; D053471:Caspases, Initiator; D006801:Humans; D015398:Signal Transduction
chemical_list: D053478:Apoptosomes; D053453:Caspase 9; D053471:Caspases, Initiator