Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism

被引：120

作者：

Barclay, Lauren A. ^{[1
,2
]}

Wales, Thomas E. ^{[3
]}

Garner, Thomas P. ^{[4
]}

Wachter, Franziska ^{[1
,2
]}

Lee, Susan ^{[1
,2
]}

Guerra, Rachel M. ^{[1
,2
]}

Stewart, Michelle L. ^{[1
,2
]}

Braun, Craig R. ^{[1
,2
]}

Bird, Gregory H. ^{[1
,2
]}

Gavathiotis, Evripidis ^{[4
]}

Engen, John R. ^{[3
]}

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

机构：

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

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

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

[4] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA

来源：

MOLECULAR CELL | 2015年 / 57卷 / 05期

关键词：

BCL-2; FAMILY; BIOPHYSICAL CHARACTERIZATION; PROTEIN INTERACTIONS; HYDROGEN-EXCHANGE; MASS-SPECTROMETRY; PROAPOPTOTIC BAX; BH4; DOMAIN; IN-VIVO; ACTIVATION; PEPTIDES;

D O I：

10.1016/j.molcel.2015.01.014

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：

BCL-2 is a negative regulator of apoptosis implicated in homeostatic and pathologic cell survival. The canonical anti-apoptotic mechanism involves entrapment of activated BAX by a groove on BCL-2, preventing BAX homo-oligomerization and mitochondrial membrane poration. The BCL-2 BH4 domain also confers anti-apoptotic functionality, but the mechanism is unknown. We find that a synthetic a-helical BH4 domain binds to BAX with nanomolar affinity and independently inhibits the conformational activation of BAX. Hydrogen-deuterium exchange mass spectrometry demonstrated that the N-terminal conformational changes in BAX induced by a triggering BIM BH3 helix were suppressed by the BCL-2 BH4 helix. Structural analyses localized the BH4 interaction site to a groove formed by residues of alpha 1, alpha 1-alpha 2 loop, and alpha 2-alpha 3 and alpha 5-alpha 6 hairpins on the BAX surface. These data reveal a previously unappreciated binding site for targeted inhibition of BAX and suggest that the BCL-2 BH4 domain may participate in apoptosis blockade by a noncanonical interaction mechanism.

引用

页码：873 / 886

页数：14

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