TY - JOUR
T1 - Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3
AU - Edwards, Amanda L.
AU - Gavathiotis, Evripidis
AU - Labelle, James L.
AU - Braun, Craig R.
AU - Opoku-Nsiah, Kwadwo A.
AU - Bird, Gregory H.
AU - Walensky, Loren D.
N1 - Funding Information:
We thank E. Smith for editorial and graphics assistance, R. George and T. Look for neuroblastoma cell lines, and D. Andrews for guidance on the liposomal assay system. This work was supported by grants from the National Institutes of Health (5R01CA050239 and 5R01GM090299), a Stand Up to Cancer Innovative Research Grant (to L.D.W.), and a National Science Foundation Graduate Research Fellowship (to A.L.E.). L.D.W. is a scientific advisory board member and consultant for Aileron Therapeutics.
PY - 2013/7/25
Y1 - 2013/7/25
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chembiol.2013.06.007
DO - 10.1016/j.chembiol.2013.06.007
M3 - Article
C2 - 23890007
AN - SCOPUS:84880911153
SN - 1074-5521
VL - 20
SP - 888
EP - 902
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 7
ER -
