7OFM

NMR structure of the Bak transmembrane helix in DPC micelles

7OFM の概要

• エントリーDOI: 10.2210/pdb7ofm/pdb
• NMR情報: BMRB: 34621
• 分子名称: Bcl-2 homologous antagonist/killer (1 entity in total)
• 機能のキーワード: mitochondria, pore formation, bcl2 proteins, apoptosis
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 3244.94

構造登録者

Sperl, L.E.,Hagn, F. (登録日: 2021-05-05, 公開日: 2021-06-23, 最終更新日: 2024-06-19)

主引用文献

Sperl, L.E.,Ruhrnossl, F.,Schiller, A.,Haslbeck, M.,Hagn, F.
High-resolution analysis of the conformational transition of pro-apoptotic Bak at the lipid membrane.
Embo J., 40:e107159-e107159, 2021

PubMed Abstract: 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.

PubMed: 34523144
DOI: 10.15252/embj.2020107159

実験手法

SOLUTION NMR