期刊
PROTEIN SCIENCE
卷 20, 期 1, 页码 62-74出版社
WILEY
DOI: 10.1002/pro.536
关键词
Bcl-2 proteins; C. elegans; protein amphitropism; mitochondrial apoptosis; mitochondrial morphology; membrane fusion; fusion protein; phospholipid vesicle
资金
- NIH [R01GM067180, 2T32GM007231]
- American Cancer Society [IRG-58-005-41]
- JHU
- Department of Defense NDSEG
- Millipore Foundation
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR020922] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007231, R01GM067180] Funding Source: NIH RePORTER
Bcl-2 proteins associate with and remodel mitochondria to regulate apoptosis. While the C. elegans Bcl-2 homolog CED-9 constitutively associates with mitochondria, it is unclear whether or not this association reflects an innate ability of CED-9 to directly remodel mitochondrial membranes. To address this question, we have characterized the effects of recombinantly expressed and purified CED-9 on synthetic lipid vesicles. We found that CED-9 associates with anionic lipid vesicles at neutral pH, and that association can occur independently of the C-terminal transmembrane domain. Membrane association changes the environment of CED-9 tryptophans and results in an apparent increase in alpha-helical structure. Upon association, CED-9 alters the permeability of membranes resulting in leakage of encapsulated dyes. Furthermore, this membrane remodeling promotes membrane fusion upon protonation of CED-9. Bypass of this protonation trigger can be achieved by mutating two conserved glutamates (E187K/E190K) or removing the N-terminal 67 residues. Together, these in vitro results suggest that CED-9 retains the amphitropic ability of mammalian Bcl-2 proteins to associate with cellular membranes. We therefore discuss the possibility that CED-9 and other Bcl-2 homologs localize at mitochondria to regulate mitochondrial homeostasis by either modulating mitochondrial membrane permeability or fusion.
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