Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane

Mingzhen Zhang, Jie Zheng, Ruth Nussinov*, Buyong Ma

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Dysfunction of Bax, a pro-apoptotic regulator of cellular metabolism is implicated in neurodegenerative diseases and cancer. We have constructed the first atomistic models of the Bax oligomeric pore consisting with experimental residue-residue distances. The models are stable, capturing well double electron-electron resonance (DEER) spectroscopy measurements and provide structural details in line with the DEER data. Comparison with the latest experimental results revealed that our models agree well with both Bax and Bak pores, pointed to a converged structural arrangement for Bax and Bak pore formation. Using multi-scale molecular dynamics simulations, we probed mutational effects on Bax transformation from monomer → dimer → membrane pore formation at atomic resolution. We observe that two cancer-related mutations, G40E and S118I, allosterically destabilize the monomer and stabilize an off-pathway swapped dimer, preventing productive pore formation. This observation suggests a mechanism whereby the mutations may work mainly by over-stabilizing the monomer → dimer transformation toward an unproductive off-pathway swapped-dimer state. Our observations point to misfolded Bax states, shedding light on the molecular mechanism of Bax mutation-elicited cancer. Most importantly, the structure of the Bax pore facilitates future study of releases cytochrome C in atomic detail.

Original languageEnglish
Article number33340
JournalScientific Reports
Volume6
DOIs
StatePublished - 15 Sep 2016

Funding

FundersFunder number
Alzheimer Association -2015-NIRG-341372
Center for Cancer Research
U.S. Government
National Science FoundationCBET-0952624, CBET-1510099
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010441
Department of Health, Australian Government

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