Reprieval from execution: the molecular basis of caspase inhibition

• Published in: Trends in Biochemical Sciences 2002-02, Vol.27 (2), p.94-101
• Main Authors: Stennicke, Henning R, Ryan, Ciara A, Salvesen, Guy S
• Format: Article
• Language: English
• Subjects: apoptosis; Apoptosis - drug effects; Apoptosis - physiology; caspase; Caspase Inhibitors; Caspases - physiology; Cysteine Proteinase Inhibitors - physiology; Enzyme Inhibitors - pharmacology; Humans; Nucleopolyhedrovirus - chemistry; p35; protease inhibitor; Protein Structure, Secondary; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; Serpins - physiology; Signal Transduction; Viral Proteins - chemistry; Viral Proteins - pharmacology; X-Linked Inhibitor of Apoptosis Protein; XIAP
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/S0968-0004(01)02045-X

The suppression of apoptosis is essential to the propagation of viruses, and to the control of development and homeostasis in insects and mammals. The central components of all apoptotic pathways are proteases of the caspase family. Therefore, it is not surprising that the processes of natural selection, as well as pharmaceutical chemists, have designed compounds that directly target caspase activity in attempts to regulate apoptosis. The mechanisms used by highly specialized naturally occurring caspase inhibitors (both host and viral) have remained obscure for some time. However, recently there has been significant progress in this field, particularly because of the structural elucidation of the complexes between caspases and an endogenous inhibitor (XIAP) and a viral inhibitor (p35). This article reviews the newly defined molecular basis for the regulation of the caspases by viral and endogenous inhibitors. Apoptosis is driven by proteolytic enzymes of the caspase family, and recent structural evidence has revealed the distinct mechanisms by which their natural protein inhibitors regulate cell death.