RT Journal Article
SR Electronic
T1 The carboxyl-terminal sequence of Bim enables Bax activation and killing of unprimed cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 554907
DO 10.1101/554907
A1 Chi, Xiaoke
A1 Nguyen, Dang
A1 Pemberton, James M
A1 Osterlund, Elizabeth J
A1 Liu, Qian
A1 Brahmbhatt, Hetal
A1 Zhang, Zhi
A1 Lin, Jialing
A1 Leber, Brian
A1 Andrews, David W.
YR 2019
UL http://biorxiv.org/content/early/2019/02/19/554907.abstract
AB The Bcl-2 family BH3 protein Bim promotes apoptosis at mitochondria by activating the pore forming proteins Bax and Bak and by inhibiting the anti-apoptotic proteins Bcl-XL, Bcl-2 and Mcl-1. Bim binds to these proteins via its BH3 domain and to the mitochondrial membrane by a carboxyl-terminal sequence (CTS). In cells killed by Bim, the expression of a Bim mutant in which the CTS was deleted (BimL-dCTS) triggered variable amounts of apoptosis that correlated with inhibition of anti-apoptotic proteins being sufficient to permeabilize mitochondria isolated from the same cells. Detailed analysis of the molecular mechanism demonstrated that BimL-dCTS inhibited Bcl-XL but did not activate Bax. Our examination of additional point mutants unexpectedly revealed that the CTS of Bim is required for physiological concentrations of Bim to activate Bax and that different residues in the CTS enable Bax activation and binding to membranes.