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Title: The X-ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site

Abstract

BAK/BAX-mediated mitochondrial outer-membrane permeabilization (MOMP) drives cell death during development and tissue homeostasis from zebrafish to humans. In most cancers, this pathway is inhibited by BCL-2 family antiapoptotic members, which bind and block the action of proapoptotic BCL proteins. We report the 1.5 {angstrom} crystal structure of calpain-proteolysed BAK, cBAK, to reveal a zinc binding site that regulates its activity via homodimerization. cBAK contains an occluded BH3 peptide binding pocket that binds a BID BH3 peptide only weakly . Nonetheless, cBAK requires activation by truncated BID to induce cytochrome c release in mitochondria isolated from bak/bax double-knockout mouse embryonic fibroblasts. The BAK-mediated MOMP is inhibited by low micromolar zinc levels. This inhibition is alleviated by mutation of the zinc-coordination site in BAK. Our results link directly the antiapoptotic effects of zinc to BAK.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930199
Report Number(s):
BNL-80862-2008-JA
TRN: US200822%%1379
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cell; Journal Volume: 24
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; CYTOCHROMES; DEATH; FIBROBLASTS; HOMEOSTASIS; HUMAN POPULATIONS; INHIBITION; LEVELS; MITOCHONDRIA; MUTATIONS; PEPTIDES; PROPOSALS; PROTEINS; ZINC; national synchrotron light source

Citation Formats

Modoveanu,T., Liu, Q., Tocilj, A., Watson, M., Shore, G., and Gehring, K. The X-ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site. United States: N. p., 2006. Web. doi:10.1016/j.molcel.2006.10.014.
Modoveanu,T., Liu, Q., Tocilj, A., Watson, M., Shore, G., & Gehring, K. The X-ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site. United States. doi:10.1016/j.molcel.2006.10.014.
Modoveanu,T., Liu, Q., Tocilj, A., Watson, M., Shore, G., and Gehring, K. Sun . "The X-ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site". United States. doi:10.1016/j.molcel.2006.10.014.
@article{osti_930199,
title = {The X-ray Structure of a BAK Homodimer Reveals an Inhibitory Zinc Binding Site},
author = {Modoveanu,T. and Liu, Q. and Tocilj, A. and Watson, M. and Shore, G. and Gehring, K.},
abstractNote = {BAK/BAX-mediated mitochondrial outer-membrane permeabilization (MOMP) drives cell death during development and tissue homeostasis from zebrafish to humans. In most cancers, this pathway is inhibited by BCL-2 family antiapoptotic members, which bind and block the action of proapoptotic BCL proteins. We report the 1.5 {angstrom} crystal structure of calpain-proteolysed BAK, cBAK, to reveal a zinc binding site that regulates its activity via homodimerization. cBAK contains an occluded BH3 peptide binding pocket that binds a BID BH3 peptide only weakly . Nonetheless, cBAK requires activation by truncated BID to induce cytochrome c release in mitochondria isolated from bak/bax double-knockout mouse embryonic fibroblasts. The BAK-mediated MOMP is inhibited by low micromolar zinc levels. This inhibition is alleviated by mutation of the zinc-coordination site in BAK. Our results link directly the antiapoptotic effects of zinc to BAK.},
doi = {10.1016/j.molcel.2006.10.014},
journal = {Molecular Cell},
number = ,
volume = 24,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}