Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization

被引：36

作者：

Hauseman, Zachary J. ^{[1
,2
]}

Harvey, Edward P. ^{[1
,2
]}

Newman, Catherine E. ^{[1
,2
]}

Wales, Thomas E. ^{[3
]}

Bucci, Joel C. ^{[3
]}

Mintseris, Julian ^{[4
]}

Schweppe, Devin K. ^{[4
]}

David, Liron ^{[5
,6
]}

Fan, Lixin ^{[7
]}

Cohen, Daniel T. ^{[1
,2
]}

Herce, Henry D. ^{[1
,2
]}

Mourtada, Rida ^{[1
,2
]}

Ben-Nun, Yael ^{[1
,2
]}

Bloch, Noah B. ^{[1
,2
]}

Hansen, Scott B. ^{[8
]}

Wu, Hao ^{[5
,6
]}

Gygi, Steven P. ^{[4
]}

Engen, John R. ^{[3
]}

Walensky, Loren D. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, Linde Program Canc Chem Biol, 450 Brookline Ave, Boston, MA 02215 USA

[3] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[6] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA

[7] Frederick Natl Lab Canc Res, Small Angle Xray Scattering Core, Frederick, MD 21702 USA

[8] Scripps Res Inst Florida, Jupiter, FL 33458 USA

来源：

MOLECULAR CELL | 2020年 / 79卷 / 01期

关键词：

BCL-2 PROTEIN FAMILY; BH3; DOMAINS; ANTIMICROBIAL PEPTIDES; CROSS-LINKING; IN-VIVO; ACTIVATION; INHIBITOR; MASS; RESOLUTION; CHANNEL;

D O I：

10.1016/j.molcel.2020.05.029

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

BAX is a pro-apoptotic protein that transforms from a cytosolic monomer into a toxic oligomer that permeabilizes the mitochondrial outer membrane. How BAX monomers assemble into a higher-order conformation, and the structural determinants essential to membrane permeabilization, remain a mechanistic mystery. A key hurdle has been the inability to generate a homogeneous BAX oligomer (BAX(O)) for analysis. Here, we report the production and characterization of a full-length BAX(O) that recapitulates physiologic BAX activation. Multidisciplinary studies revealed striking conformational consequences of oligomerization and insight into the macromolecular structure of oligomeric BAX. Importantly, BAX(O) enabled the assignment of specific roles to particular residues and alpha helices that mediate individual steps of the BAX activation pathway, including unexpected functionalities of BAX alpha 6 and alpha 9 in driving membrane disruption. Our results provide the first glimpse of a full-length and functional BAX(O), revealing structural requirements for the elusive execution phase of mitochondrial apoptosis.

引用

页码：68 / +

页数：23

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