The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition

The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition

Author Shin, Hwain Google Scholar
Renatus, Martin Google Scholar
Eckelman, Brendan P. Google Scholar
Nunes, Viviane Abreu Autor UNIFESP Google Scholar
Sampaio, Claudio Augusto Machado Autor UNIFESP Google Scholar
Salvesen, Guy S. Google Scholar
Institution Burnham Inst
Univ Calif San Diego
Universidade Federal de São Paulo (UNIFESP)
Abstract Several IAP (inhibitor of apoptosis) proteins regulate cell fate decisions, and the X-linked IAP (XIAP) does so in part by inhibiting caspases, proteases that execute the apoptotic pathway. A tissue-specific homologue of XIAP, known as ILP2 (IAP-like protein 2), has previously been implicated in the control of apoptosis in the testis by direct inhibition of caspase 9. in examining this protein we found that the putative caspase 9 interaction domain is a surprisingly weak inhibitor and is also conformationally unstable. Comparison with the equivalent domain in XIAP demonstrated that the instability is due to the lack of a linker segment N-terminal to the inhibitory BIR (baculovirus IAP repeat) domain. Fusion of a 9-residue linker from XIAP to the N-terminus of ILP2 restored tight caspase 9 inhibition, dramatically increased conformational stability and allowed crystallization of the ILP2 BIR domain in a form strikingly similar to the XIAP third BIR domain. We conclude that ILP2 is an unstable protein, and cannot inhibit caspase 9 in a physiological way on its own. We speculate that ILP2 requires assistance from unidentified cellular factors to be an effective inhibitor of apoptosis in vivo.
Keywords apoptosis
baculovirus IAP repeat (BIR) domain
caspase
crystallography
inhibitor of apoptosis protein (IAP)
spermatogenesis
Language English
Date 2005-01-01
Published in Biochemical Journal. London: Portland Press, v. 385, p. 1-10, 2005.
ISSN 0264-6021 (Sherpa/Romeo, impact factor)
Publisher Portland Press
Extent 1-10
Origin http://dx.doi.org/10.1042/BJ20041107
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000226346500001
URI http://repositorio.unifesp.br/handle/11600/28055

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