title: Bak Conformational Changes Induced by Ligand Binding: Insight into BH3 Domain Binding and Bak Homo-Oligomerization.
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.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.forename: Alyson
authors.initials: A
authors.lastname: Smith
authors.forename: X Wei
authors.initials: XW
authors.lastname: Meng
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann