1tw6

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{{STRUCTURE_1tw6| PDB=1tw6 | SCENE= }}
{{STRUCTURE_1tw6| PDB=1tw6 | SCENE= }}
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'''Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac'''
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===Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac===
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==Overview==
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ML-IAP (melanoma inhibitor of apoptosis) is a potent anti-apoptotic protein that is strongly up-regulated in melanoma and confers protection against a variety of pro-apoptotic stimuli. The mechanism by which ML-IAP regulates apoptosis is unclear, although weak inhibition of caspases 3 and 9 has been reported. Here, the binding to and inhibition of caspase 9 by the single BIR (baculovirus IAP repeat) domain of ML-IAP has been investigated and found to be significantly less potent than the ubiquitously expressed XIAP (X-linked IAP). Engineering of the ML-IAP-BIR domain, based on comparisons with the third BIR domain of XIAP, resulted in a chimeric BIR domain that binds to and inhibits caspase 9 significantly better than either ML-IAP-BIR or XIAP-BIR3. Mutational analysis of the ML-IAP-BIR domain demonstrated that similar enhancements in caspase 9 affinity can be achieved with only three amino acid substitutions. However, none of these modifications affected binding of the ML-IAP-BIR domain to the IAP antagonist Smac (second mitochondrial activator of caspases). ML-IAP-BIR was found to bind mature Smac with low nanomolar affinity, similar to that of XIAP-BIR2-BIR3. Correspondingly, increased expression of ML-IAP results in formation of a ML-IAP-Smac complex and disruption of the endogenous interaction between XIAP and mature Smac. These results suggest that ML-IAP might regulate apoptosis by sequestering Smac and preventing it from antagonizing XIAP-mediated inhibition of caspases, rather than by direct inhibition of caspases.
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The line below this paragraph, {{ABSTRACT_PUBMED_15485396}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 15485396 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15485396}}
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP., Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ, Biochem J. 2005 Jan 1;385(Pt 1):11-20. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15485396 15485396]
Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP., Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ, Biochem J. 2005 Jan 1;385(Pt 1):11-20. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15485396 15485396]
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Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP)., Franklin MC, Kadkhodayan S, Ackerly H, Alexandru D, Distefano MD, Elliott LO, Flygare JA, Mausisa G, Okawa DC, Ong D, Vucic D, Deshayes K, Fairbrother WJ, Biochemistry. 2003 Jul 15;42(27):8223-31. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12846571 12846571]
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Mechanism of XIAP-mediated inhibition of caspase-9., Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y, Mol Cell. 2003 Feb;11(2):519-27. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12620238 12620238]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Peptide complex]]
[[Category: Peptide complex]]
[[Category: Zinc binding]]
[[Category: Zinc binding]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:26:40 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 20:25:17 2008''

Revision as of 17:25, 27 July 2008

Image:1tw6.png

Template:STRUCTURE 1tw6

Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac

Template:ABSTRACT PUBMED 15485396

About this Structure

1TW6 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP., Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ, Biochem J. 2005 Jan 1;385(Pt 1):11-20. PMID:15485396

Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP)., Franklin MC, Kadkhodayan S, Ackerly H, Alexandru D, Distefano MD, Elliott LO, Flygare JA, Mausisa G, Okawa DC, Ong D, Vucic D, Deshayes K, Fairbrother WJ, Biochemistry. 2003 Jul 15;42(27):8223-31. PMID:12846571

Mechanism of XIAP-mediated inhibition of caspase-9., Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y, Mol Cell. 2003 Feb;11(2):519-27. PMID:12620238

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