Chapter category: Apoptosis

Mitochondrial/Apoptosome Dependent Activation of Caspases

This chapter appears in the following book:

Caspases: Their Role in Cell Death and Cell Survival

Edited by: Marek Los and Henning Walczak
ISBN: 0-306-47441-7
» Get more information about this book at landesbioscience.com «

Chapter authors:
Kelvin Cain

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Many key biological processes, including caspase activation during apoptotic cell death are executed by large multi-protein complexes. Apoptosis can be initiated via death receptors or by perturbation of the mitochondria, which results in the release of apoptogenic proteins. These initiate and promote the activation of the caspases, which produce the biochemical and morphological changes that are characteristic of apoptotic cell death. Caspases are normally present as inactive zymogens, and require specific proteolytic cleavage for activity. This activation process occurs in large specialised protein complexes known as the DISC (receptor mediated cell death) and the apoptosome (mitochondrial mediated cell death) that are assembled de nouveau when apoptosis is initiated. In mammals the central scaffold protein of the apoptosome is an ~130 kD protein known as Apaf-1 which is a homologue of CED-4, a key protein involved in programmed cell death in the nematode C.elegans. Apaf-1 in the presence of cytochrome c and dATP oligomerizes to form a very large (~700 to 1400 kD) apoptosome complex, which recruits and activates/processes caspase-9 to form the active caspase processing holoenzyme complex that subsequently recruits and activates the effector caspases. The apoptosome has been described in cells undergoing apoptosis, in dATP activated cell lysates and in reconstitution studies with recombinant proteins. Recent studies show that formation and function of the apoptosome is tightly regulated by intracellular levels of K⁺, inhibitor of apoptosis proteins (IAPs), heat shock proteins and at least two mitochondrialreleased proteins, Smac/Diablo and Omi/Htra 2 a serine protease. Thus, a variety of factors ensure that the apoptosome complex is only fully assembled and functional when the cell is irrevocably destined to die.

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Chapter category: Apoptosis

Mitochondrial/Apoptosome Dependent Activation of Caspases

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