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Sperl, L.E. ; Rührnößl, F.* ; Schiller, A. ; Haslbeck, M.* ; Hagn, F.

High-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane.

EMBO J.:e107159 (2021)

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	Open Access Gold (Paid Option)

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Permeabilization of the outer mitochondrial membrane by pore-forming Bcl2 proteins is a crucial step for the induction of apoptosis. Despite a large set of data suggesting global conformational changes within pro-apoptotic Bak during pore formation, high-resolution structural details in a membrane environment remain sparse. Here, we used NMR and HDX-MS (Hydrogen deuterium exchange mass spectrometry) in lipid nanodiscs to gain important high-resolution structural insights into the conformational changes of Bak at the membrane that are dependent on a direct activation by BH3-only proteins. Furthermore, we determined the first high-resolution structure of the Bak transmembrane helix. Upon activation, α-helix 1 in the soluble domain of Bak dissociates from the protein and adopts an unfolded and dynamic potentially membrane-bound state. In line with this finding, comparative protein folding experiments with Bak and anti-apoptotic BclxL suggest that α-helix 1 in Bak is a metastable structural element contributing to its pro-apoptotic features. Consequently, mutagenesis experiments aimed at stabilizing α-helix 1 yielded Bak variants with delayed pore-forming activity. These insights will contribute to a better mechanistic understanding of Bak-mediated membrane permeabilization.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Apoptosis ; Hdx-ms ; Lipid Nanodiscs ; Membrane ; Nmr; Phospholipid-bilayer Nanodiscs; Bh3 Domains; Bcl-xl; Proteins; Pore; Activation; Oligomerization; Insertion; Helix; Translocation

ISSN (print) / ISBN 0261-4189

e-ISSN 1460-2075

Journal EMBO Journal, The

Quellenangaben Article Number: e107159

Publisher Wiley

Publishing Place Heidelberg, Germany

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)

Grants Deutsche Forschungsgemeinschaft (DFG)
Helmholtz Association ()