Bak conformational changes induced by ligand binding: Insight into BH3 domain binding and bak homo-oligomerization

Yuan Ping Pang, Haiming Dai, Alyson Smith, X. Wei Meng, Paula A. Schneider, Scott H. Kaufmann

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Recently we reported that the BH3-only proteins Bim and Noxa bind tightly but transiently to the BH3-binding groove of Bak to initiate Bak homo-oligomerization. However, it is unclear how such tight binding can induce Bak homo-oligomerization. Here we report the ligand-induced Bak conformational changes observed in 3D models of Noxa·Bak and Bim·Bak refined by molecular dynamics simulations. In particular, upon binding to the BH3-binding groove, Bim and Noxa induce a large conformational change of the loop between helices 1 and 2 and in turn partially expose a remote groove between helices 1 and 6 in Bak. These observations, coupled with the reported experimental data, suggest formation of a pore-forming Bak octamer, in which the BH3-binding groove is at the interface on one side of each monomer and the groove between helices 1 and 6 is at the interface on the opposite side, initiated by ligand binding to the BH3-binding groove.

Original languageEnglish (US)
Article number257
JournalScientific reports
Volume2
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • General

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