title: Oncogenic Mutations Differentially Affect Bax Monomer, Dimer, and Oligomeric Pore Formation in the Membrane.
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.
authors.affiliation: Department of Chemical &Biomolecular Engineering, the University of Akron, Akron, Ohio 44325.
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Chemical &Biomolecular Engineering, the University of Akron, Akron, Ohio 44325.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.|Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045304:Cytochromes c / Q000737:chemistry / Q000235:genetics; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008566:Membranes / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D052899:Pore Forming Cytotoxic Proteins / Q000737:chemistry / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics*; D017434:Protein Structure, Tertiary; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D052899:Pore Forming Cytotoxic Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c