Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

Jenson, Justin M.; Ryan, Jeremy A.; Grant, Robert A.; Letai, Anthony; Keating, Amy E.

doi:10.7554/eLife.25541

Title: Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

Journal Article · Thu Jun 08 00:00:00 EDT 2017 · eLife

DOI:https://doi.org/10.7554/eLife.25541· OSTI ID:1368344

^[1];

^[2]; Grant, Robert A. ^[1]; Letai, Anthony ^[2];

^[1]

Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Dana-Farber Cancer Institute, Boston, MA (United States)

Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of General Medical Sciences; National Inst. of Health; NIH-ORIP HEI; National Science Foundation (NSF); MIT School of Science Ludwig Fund for Cancer Research; Koch Institute/MIT - Dana-Farber/Harvard Cancer Center Bridge Project

Grant/Contract Number:: AC02-06CH11357; P41 GM103403; S10 RR029205; R01-GM110048

OSTI ID:: 1368344

Journal Information:: eLife, Vol. 6, Issue 2017; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 27 works

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References (63)

Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines Koss, Brian; Ryan, Jeremy; Budhraja, Amit Oncotarget, Vol. 7, Issue 10 https://doi.org/10.18632/oncotarget.7204	journal	February 2016
Peptide Ligands for Pro-survival Protein Bfl-1 from Computationally Guided Library Screening Dutta, Sanjib; Chen, T. Scott; Keating, Amy E. ACS Chemical Biology, Vol. 8, Issue 4 https://doi.org/10.1021/cb300679a	journal	February 2013
Pretreatment Mitochondrial Priming Correlates with Clinical Response to Cytotoxic Chemotherapy Chonghaile, T. N.; Sarosiek, K. A.; Vo, T. -T. Science, Vol. 334, Issue 6059 https://doi.org/10.1126/science.1206727	journal	October 2011
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models Kotschy, András; Szlavik, Zoltán; Murray, James Nature, Vol. 538, Issue 7626 https://doi.org/10.1038/nature19830	journal	October 2016
Inhibition of Bfl-1 with N-aryl maleimides Cashman, John R.; MacDonald, Mary; Ghirmai, Senait Bioorganic & Medicinal Chemistry Letters, Vol. 20, Issue 22 https://doi.org/10.1016/j.bmcl.2010.09.046	journal	November 2010
Multimodal Interaction with BCL-2 Family Proteins Underlies the Proapoptotic Activity of PUMA BH3 Edwards, Amanda L.; Gavathiotis, Evripidis; LaBelle, James L. Chemistry & Biology, Vol. 20, Issue 7 https://doi.org/10.1016/j.chembiol.2013.06.007	journal	July 2013
Bcl-xL–inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets Schoenwaelder, Simone M.; Jarman, Kate E.; Gardiner, Elizabeth E. Blood, Vol. 118, Issue 6 https://doi.org/10.1182/blood-2011-04-347849	journal	August 2011
Isolating and engineering human antibodies using yeast surface display Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J. Nature Protocols, Vol. 1, Issue 2 https://doi.org/10.1038/nprot.2006.94	journal	July 2006
Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer Rudin, C. M.; Hann, C. L.; Garon, E. B. Clinical Cancer Research, Vol. 18, Issue 11 https://doi.org/10.1158/1078-0432.CCR-11-3090	journal	April 2012
Role of the pro-survival molecule Bfl-1 in melanoma Hind, C. K.; Carter, M. J.; Harris, C. L. The International Journal of Biochemistry & Cell Biology, Vol. 59 https://doi.org/10.1016/j.biocel.2014.11.015	journal	February 2015
MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family Beverly, L. J.; Varmus, H. E. Oncogene, Vol. 28, Issue 9 https://doi.org/10.1038/onc.2008.466	journal	January 2009
Evaluation of the BH3-only Protein Puma as a Direct Bak Activator Dai, Haiming; Pang, Yuan-Ping; Ramirez-Alvarado, Marina Journal of Biological Chemistry, Vol. 289, Issue 1 https://doi.org/10.1074/jbc.M113.505701	journal	November 2013
Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins Foight, Glenna Wink; Keating, Amy E. Journal of Molecular Biology, Vol. 427, Issue 15 https://doi.org/10.1016/j.jmb.2015.05.015	journal	July 2015
BH3 profiling in whole cells by fluorimeter or FACS Ryan, Jeremy; Letai, Anthony Methods, Vol. 61, Issue 2 https://doi.org/10.1016/j.ymeth.2013.04.006	journal	June 2013
Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737 Mathieu, Anne-Laure; Sperandio, Olivier; Pottiez, Virginie Journal of Biomolecular Screening, Vol. 19, Issue 7 https://doi.org/10.1177/1087057114534070	journal	August 2014
Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices Bird, Gregory H.; Mazzola, Emanuele; Opoku-Nsiah, Kwadwo Nature Chemical Biology, Vol. 12, Issue 10 https://doi.org/10.1038/nchembio.2153	journal	August 2016
Genome-Wide Prediction and Validation of Peptides That Bind Human Prosurvival Bcl-2 Proteins DeBartolo, Joe; Taipale, Mikko; Keating, Amy E. PLoS Computational Biology, Vol. 10, Issue 6 https://doi.org/10.1371/journal.pcbi.1003693	journal	June 2014
Heightened mitochondrial priming is the basis for apoptotic hypersensitivity of CD4+ CD8+ thymocytes Ryan, J. A.; Brunelle, J. K.; Letai, A. Proceedings of the National Academy of Sciences, Vol. 107, Issue 29 https://doi.org/10.1073/pnas.0914878107	journal	July 2010
An inhibitor of Bcl-2 family proteins induces regression of solid tumours Oltersdorf, Tilman; Elmore, Steven W.; Shoemaker, Alexander R. Nature, Vol. 435, Issue 7042 https://doi.org/10.1038/nature03579	journal	May 2005
Structural Plasticity Underpins Promiscuous Binding of the Prosurvival Protein A1 Smits, Callum; Czabotar, Peter E.; Hinds, Mark G. Structure, Vol. 16, Issue 5 https://doi.org/10.1016/j.str.2008.02.009	journal	May 2008
Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design Foight, Glenna Wink; Chen, T. Scott; Richman, Daniel Methods in Molecular Biology https://doi.org/10.1007/978-1-4939-6798-8_13	book	January 2017
Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix Walensky, L. D. Science, Vol. 305, Issue 5689 https://doi.org/10.1126/science.1099191	journal	September 2004
BH3 Profiling Identifies Three Distinct Classes of Apoptotic Blocks to Predict Response to ABT-737 and Conventional Chemotherapeutic Agents Deng, Jing; Carlson, Nicole; Takeyama, Kunihiko Cancer Cell, Vol. 12, Issue 2 https://doi.org/10.1016/j.ccr.2007.07.001	journal	August 2007
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia Roberts, Andrew W.; Davids, Matthew S.; Pagel, John M. New England Journal of Medicine, Vol. 374, Issue 4 https://doi.org/10.1056/NEJMoa1513257	journal	January 2016
BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition Haq, Rizwan; Yokoyama, Satoru; Hawryluk, Elena B. Proceedings of the National Academy of Sciences, Vol. 110, Issue 11 https://doi.org/10.1073/pnas.1205575110	journal	February 2013
Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics Letai, Anthony; Bassik, Michael C.; Walensky, Loren D. Cancer Cell, Vol. 2, Issue 3 https://doi.org/10.1016/S1535-6108(02)00127-7	journal	September 2002
A General Framework for Development and Data Analysis of Competitive High-Throughput Screens for Small-Molecule Inhibitors of Protein−Protein Interactions by Fluorescence Polarization ^† Roehrl, Michael H. A.; Wang, Julia Y.; Wagner, Gerhard Biochemistry, Vol. 43, Issue 51 https://doi.org/10.1021/bi048233g	journal	December 2004
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets Souers, Andrew J.; Leverson, Joel D.; Boghaert, Erwin R. Nature Medicine, Vol. 19, Issue 2 https://doi.org/10.1038/nm.3048	journal	January 2013
Electrophilic Helical Peptides That Bond Covalently, Irreversibly, and Selectively in a Protein–Protein Interaction Site de Araujo, Aline Dantas; Lim, Junxian; Good, Andrew C. ACS Medicinal Chemistry Letters, Vol. 8, Issue 1 https://doi.org/10.1021/acsmedchemlett.6b00395	journal	November 2016
Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors Huhn, Annissa J.; Guerra, Rachel M.; Harvey, Edward P. Cell Chemical Biology, Vol. 23, Issue 9 https://doi.org/10.1016/j.chembiol.2016.07.022	journal	September 2016
Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains Rezaei Araghi, Raheleh; Ryan, Jeremy A.; Letai, Anthony ACS Chemical Biology, Vol. 11, Issue 5 https://doi.org/10.1021/acschembio.5b01002	journal	February 2016
hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anticancer Agents Barile, Elisa; Marconi, Guya D.; De, Surya K. ACS Chemical Biology, Vol. 12, Issue 2 https://doi.org/10.1021/acschembio.6b00962	journal	December 2016
Mcl-1- Bim complexes accommodate surprising point mutations via minor structural changes Fire, Emiko; Gullá, Stefano V.; Grant, Robert A. Protein Science https://doi.org/10.1002/pro.329	journal	January 2010
Predictive Bcl-2 Family Binding Models Rooted in Experiment or Structure DeBartolo, Joe; Dutta, Sanjib; Reich, Lothar Journal of Molecular Biology, Vol. 422, Issue 1 https://doi.org/10.1016/j.jmb.2012.05.022	journal	September 2012
Drug-Induced Death Signaling Strategy Rapidly Predicts Cancer Response to Chemotherapy Montero, Joan; Sarosiek, Kristopher A.; DeAngelo, Joseph D. Cell, Vol. 160, Issue 5 https://doi.org/10.1016/j.cell.2015.01.042	journal	February 2015
Attacking cancer's Achilles heel: antagonism of anti-apoptotic BCL-2 family members Opferman, Joseph T. The FEBS Journal, Vol. 283, Issue 14 https://doi.org/10.1111/febs.13472	journal	September 2015
Designing helical peptide inhibitors of protein–protein interactions Rezaei Araghi, Raheleh; Keating, Amy E. Current Opinion in Structural Biology, Vol. 39 https://doi.org/10.1016/j.sbi.2016.04.001	journal	August 2016
Mutation to Bax beyond the BH3 Domain Disrupts Interactions with Pro-survival Proteins and Promotes Apoptosis Czabotar, Peter E.; Lee, Erinna F.; Thompson, Geoff V. Journal of Biological Chemistry, Vol. 286, Issue 9 https://doi.org/10.1074/jbc.M110.161281	journal	January 2011
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
COBALT: constraint-based alignment tool for multiple protein sequences Papadopoulos, J. S.; Agarwala, R. Bioinformatics, Vol. 23, Issue 9 https://doi.org/10.1093/bioinformatics/btm076	journal	March 2007
Selective Induction of Cell Death in Melanoma Cell Lines through Targeting of Mcl-1 and A1 Senft, Daniela; Berking, Carola; Graf, Saskia A. PLoS ONE, Vol. 7, Issue 1 https://doi.org/10.1371/journal.pone.0030821	journal	January 2012
Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer Berger, Stephanie; Procko, Erik; Margineantu, Daciana eLife, Vol. 5 https://doi.org/10.7554/eLife.20352	journal	November 2016
Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins Zhai, Dayong; Jin, Chaofang; Shiau, Chung-wai Molecular Cancer Therapeutics, Vol. 7, Issue 6 https://doi.org/10.1158/1535-7163.MCT-07-2373	journal	June 2008
Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease Roberts, Andrew W.; Seymour, John F.; Brown, Jennifer R. Journal of Clinical Oncology, Vol. 30, Issue 5 https://doi.org/10.1200/JCO.2011.34.7898	journal	February 2012
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Conformational Changes in Bcl-2 Pro-survival Proteins Determine Their Capacity to Bind Ligands Lee, Erinna F.; Czabotar, Peter E.; Yang, Hong Journal of Biological Chemistry, Vol. 284, Issue 44 https://doi.org/10.1074/jbc.M109.040725	journal	September 2009
Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members Certo, Michael; Moore, Victoria Del Gaizo; Nishino, Mari Cancer Cell, Vol. 9, Issue 5 https://doi.org/10.1016/j.ccr.2006.03.027	journal	May 2006
iBH3: simple, fixable BH3 profiling to determine apoptotic priming in primary tissue by flow cytometry Ryan, Jeremy; Montero, Joan; Rocco, James Biological Chemistry, Vol. 397, Issue 7 https://doi.org/10.1515/hsz-2016-0107	journal	July 2016
Potent and Specific Peptide Inhibitors of Human Pro-Survival Protein Bcl-xL Dutta, Sanjib; Ryan, Jeremy; Chen, T. Scott Journal of Molecular Biology, Vol. 427, Issue 6 https://doi.org/10.1016/j.jmb.2014.09.030	journal	March 2015
Structure-Based Redesign of the Binding Specificity of Anti-Apoptotic Bcl-xL Chen, T. Scott; Palacios, Hector; Keating, Amy E. Journal of Molecular Biology, Vol. 425, Issue 1 https://doi.org/10.1016/j.jmb.2012.11.009	journal	January 2013
DNA fingerprinting of the NCI-60 cell line panel Lorenzi, P. L.; Reinhold, W. C.; Varma, S. Molecular Cancer Therapeutics, Vol. 8, Issue 4 https://doi.org/10.1158/1535-7163.MCT-08-0921	journal	April 2009
High-Throughput Fluorescence Polarization Assay for Chemical Library Screening against Anti-Apoptotic Bcl-2 Family Member Bfl-1 Zhai, Dayong; Godoi, Paulo; Sergienko, Eduard Journal of Biomolecular Screening, Vol. 17, Issue 3 https://doi.org/10.1177/1087057111429372	journal	March 2012
Downregulation of Bfl-1 protein expression sensitizes malignant B cells to apoptosis Brien, G.; Trescol-Biemont, M-C; Bonnefoy-Bérard, N. Oncogene, Vol. 26, Issue 39 https://doi.org/10.1038/sj.onc.1210363	journal	March 2007
Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim Herman, Maria Dolores; Nyman, Tomas; Welin, Martin FEBS Letters, Vol. 582, Issue 25-26 https://doi.org/10.1016/j.febslet.2008.09.028	journal	September 2008
Hierarchy and extremes in selections from pools of randomized proteins Boyer, Sébastien; Biswas, Dipanwita; Kumar Soshee, Ananda Proceedings of the National Academy of Sciences, Vol. 113, Issue 13 https://doi.org/10.1073/pnas.1517813113	journal	March 2016
Structure-guided design of a selective BCL-XL inhibitor Lessene, Guillaume; Czabotar, Peter E.; Sleebs, Brad E. Nature Chemical Biology, Vol. 9, Issue 6 https://doi.org/10.1038/nchembio.1246	journal	April 2013
In Silico and in Vitro Elucidation of BH3 Binding Specificity toward Bcl-2 London, Nir; Gullá, Stefano; Keating, Amy E. Biochemistry, Vol. 51, Issue 29 https://doi.org/10.1021/bi3003567	journal	July 2012
Designed BH3 Peptides with High Affinity and Specificity for Targeting Mcl-1 in Cells Foight, Glenna Wink; Ryan, Jeremy A.; Gullá, Stefano V. ACS Chemical Biology, Vol. 9, Issue 9 https://doi.org/10.1021/cb500340w	journal	July 2014
Hydrophile scanning as a complement to alanine scanning for exploring and manipulating protein-protein recognition: Application to the Bim BH3 domain Boersma, Melissa D.; Sadowsky, Jack D.; Tomita, York A. Protein Science, Vol. 17, Issue 7 https://doi.org/10.1110/ps.032896.107	journal	July 2008
Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma Fan, Gaofeng; Simmons, Matthew J.; Ge, Sheng Blood, Vol. 115, Issue 17 https://doi.org/10.1182/blood-2009-08-236760	journal	April 2010
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Determinants of BH3 Binding Specificity for Mcl-1 versus Bcl-xL Dutta, Sanjib; Gullá, Stefano; Chen, T. Scott Journal of Molecular Biology, Vol. 398, Issue 5 https://doi.org/10.1016/j.jmb.2010.03.058	journal	May 2010

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