Peptides targeting caspase inhibitors

Ingo Tamm, Martin Trepel, Marina Cardó-Vila, Yan Sun, Kate Welsh, Edelmira Cabezas, Arnold Swatterthwait, Wadih Arap, John C. Reed, Renata Pasqualini

Research output: Contribution to journalArticle

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Abstract

Here we report on the identification of peptides targeting the X-inhibitor of apoptosis protein (XIAP). XIAP functions as a caspase inhibitor and is a member of the inhibitors of apoptosis (IAP) family of proteins. IAPs are often overexpressed in cancers and leukemias and are associated with an unfavorable clinical prognosis. We have selected peptides from a phage library by using recombinant full-length human XIAP or a fragment containing only the baculovirus IAP repeat 2 (BIR2) domain. A consensus motif, C(D/EfP)(W/F/Y)-acid/basic-XC, was recovered from two independent screenings by using different libraries. Phage-displaying variations of the consensus sequence bound specifically to the BIR2 domain of XIAP but not to other LAPs. The interaction was specific as it could be blocked by the cognate synthetic peptides in a dose-dependent manner. Phage displaying the XIAP-binding motif CEFESC bound to the BIR2 domain of XIAP with an estimated dissociation constant of 1.8 nM as determined by surface plasmon resonance. Protein-protein interaction assays revealed that caspase-3 and caspase-7 (but not caspase-8) blocked the binding of the CEFESC phage to XIAP, indicating that this peptide targets a domain within XIAP that is related to the caspase-binding site. In fact, the sequence EFES is homologous to a loop unique to the executioner caspase-3 and caspase-7 that are targeted by XIAP. Finally, we demonstrated that an internalizing version of the XIAP-binding peptide identified in our screenings (PFKQ) can induce programmed cell death in leukemia cells. Peptides interacting with XIAP could serve as prototypes for the design of low molecular weight modulators of apoptosis.

Original languageEnglish (US)
Pages (from-to)14401-14405
Number of pages5
JournalJournal of Biological Chemistry
Volume278
Issue number16
DOIs
StatePublished - Apr 18 2003

Fingerprint

Inhibitor of Apoptosis Proteins
Caspase Inhibitors
Peptides
Bacteriophages
Baculoviridae
Caspase 7
Apoptosis
Caspase 3
Protein Binding
Screening
Leukemia
Proteins
Caspase 8
Amino Acid Motifs
Surface plasmon resonance
Surface Plasmon Resonance
Cell death
Caspases
Consensus Sequence
Modulators

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tamm, I., Trepel, M., Cardó-Vila, M., Sun, Y., Welsh, K., Cabezas, E., ... Pasqualini, R. (2003). Peptides targeting caspase inhibitors. Journal of Biological Chemistry, 278(16), 14401-14405. https://doi.org/10.1074/jbc.M210133200

Peptides targeting caspase inhibitors. / Tamm, Ingo; Trepel, Martin; Cardó-Vila, Marina; Sun, Yan; Welsh, Kate; Cabezas, Edelmira; Swatterthwait, Arnold; Arap, Wadih; Reed, John C.; Pasqualini, Renata.

In: Journal of Biological Chemistry, Vol. 278, No. 16, 18.04.2003, p. 14401-14405.

Research output: Contribution to journalArticle

Tamm, I, Trepel, M, Cardó-Vila, M, Sun, Y, Welsh, K, Cabezas, E, Swatterthwait, A, Arap, W, Reed, JC & Pasqualini, R 2003, 'Peptides targeting caspase inhibitors', Journal of Biological Chemistry, vol. 278, no. 16, pp. 14401-14405. https://doi.org/10.1074/jbc.M210133200
Tamm I, Trepel M, Cardó-Vila M, Sun Y, Welsh K, Cabezas E et al. Peptides targeting caspase inhibitors. Journal of Biological Chemistry. 2003 Apr 18;278(16):14401-14405. https://doi.org/10.1074/jbc.M210133200
Tamm, Ingo ; Trepel, Martin ; Cardó-Vila, Marina ; Sun, Yan ; Welsh, Kate ; Cabezas, Edelmira ; Swatterthwait, Arnold ; Arap, Wadih ; Reed, John C. ; Pasqualini, Renata. / Peptides targeting caspase inhibitors. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 16. pp. 14401-14405.
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AU - Sun, Yan

AU - Welsh, Kate

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AU - Swatterthwait, Arnold

AU - Arap, Wadih

AU - Reed, John C.

AU - Pasqualini, Renata

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