Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3

Amanda L. Edwards, Evripidis Gavathiotis, James L. Labelle, Craig R. Braun, Kwadwo A. Opoku-Nsiah, Gregory H. Bird, Loren D. Walensky

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

PUMA is a proapoptotic BCL-2 family member that drives the apoptotic response to a diversity of cellular insults. Deciphering the spectrum of PUMA interactions that confer its context-dependent proapoptotic properties remains a high priority goal. Here, we report the synthesis of PUMA SAHBs, structurally stabilized PUMA BH3 helices that, in addition to broadly targeting antiapoptotic proteins, directly bind to proapoptotic BAX. NMR, photocrosslinking, and biochemical analyses revealed that PUMA SAHBs engage an α1/α6 trigger site on BAX to initiate its functional activation. We further demonstrated that a cell-permeable PUMA SAHB analog induces apoptosis in neuroblastoma cells and, like expressed PUMA protein, engages BCL-2, MCL-1, and BAX. Thus, we find that PUMA BH3 is a dual antiapoptotic inhibitor and proapoptotic direct activator, and its mimetics may serve as effective pharmacologic triggers of apoptosis in resistant human cancers.

Original languageEnglish (US)
Pages (from-to)888-902
Number of pages15
JournalChemistry and Biology
Volume20
Issue number7
DOIs
StatePublished - Jul 25 2013
Externally publishedYes

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Apoptosis
Protein Transport
Neuroblastoma
Proteins
Chemical activation
Nuclear magnetic resonance
Neoplasms
Drive

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Edwards, A. L., Gavathiotis, E., Labelle, J. L., Braun, C. R., Opoku-Nsiah, K. A., Bird, G. H., & Walensky, L. D. (2013). Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. Chemistry and Biology, 20(7), 888-902. https://doi.org/10.1016/j.chembiol.2013.06.007

Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. / Edwards, Amanda L.; Gavathiotis, Evripidis; Labelle, James L.; Braun, Craig R.; Opoku-Nsiah, Kwadwo A.; Bird, Gregory H.; Walensky, Loren D.

In: Chemistry and Biology, Vol. 20, No. 7, 25.07.2013, p. 888-902.

Research output: Contribution to journalArticle

Edwards, Amanda L. ; Gavathiotis, Evripidis ; Labelle, James L. ; Braun, Craig R. ; Opoku-Nsiah, Kwadwo A. ; Bird, Gregory H. ; Walensky, Loren D. / Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. In: Chemistry and Biology. 2013 ; Vol. 20, No. 7. pp. 888-902.
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