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.

Direct Interaction of Bax and Bak Proteins with Bcl-2 Homology Domain 3 (BH3)-only Proteins in Living Cells Revealed by Fluorescence Complementation

“…Mutation of Leu-29 to Glu abolished its binding to other proteins of the family (Fig. 7), confirming the implication of the BH3 domain in these interactions (7,40). The H1␣ of Bax, but not its BH3 domain, was necessary for Noxa-Bax association (Fig.…”

Small molecule Mcl-1 inhibitors for the treatment of cancer

“…(Korsmeyer, 1999; Pang, et al, 2012) Members within the same family can have opposite effects. The anti-apoptotic or pro-survival proteins, including Bcl-2, Bcl-X L , Bcl-w, Bfl-1/A1 and Mcl-1,(Adams & Cory, 2007) keep cells alive; whereas, the pro-apoptotic proteins (e.g., Bim, tBid, Bad, Puma, Noxa, Bak, and Bax)(Youle & Strasser, 2008) promote cell death.…”

Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis

“…35 A recent model of a Bak octameric pore was also based on a single-interface mechanism. 83 An alternative symmetric or two-interface model was proposed for Bak, based on a cysteine-linkage approach in mammalian cells 26 and was later supported for Bax in different linkage studies. 84,85 In this model, the exposed Bak BH3 domain engages the canonical hydrophobic surface groove of a partner Bak molecule in a similar manner to its interaction with the prosurvival groove.…”