The Chiang group reports evidence that the activation of apoptotic BAX can be initiated by an intrinsically disordered Bim protein through an induced-fit process.

Bcl-2-associated X (BAX) protein plays a gatekeeper role in transmitting apoptotic signaling from cytosol to mitochondria. However, little is known about its stability. This study reports a comprehensive investigation on the stability of BAX using spin-label ESR, CD, and ThermoFluor methods. Point mutations covering all of the nine helices of BAX were prepared. ESR study shows that BAX can be divided into two structural regions, each responding differently to the presence of guanidine hydrochloride (GdnHCl). The N-terminal region (helices 1−3) is denatured in 6 M GdnHCl, whereas the C-terminal region (helices 4−9) is resistant to the denaturing effects. The far-UV CD spectra show an appreciable amount of helical content of BAX at high temperatures. The magnitude of the near-UV CD signal is increased with increasing temperature in either 0 or 6 M GdnHCl, indicating an enhancement of aromatic side-chain packing in the C-terminal region. Taken together with ThermoFluor results, we show that a core interior, wherein aromatic interactions are highly involved, within the C-terminal region plays an important role in stabilizing BAX against the denaturing effects. Collectively, we report a highly stable, indestructible intermediate state of BAX. Side-chain packing interactions are shown to be the major stabilizing force in determining BAX structure.

Related references:

RSC Advances, 8 (2018) 34656-34669

Journal of Physical Chemistry B, 119 (2015) 54-64

Journal of Physical Chemistry B, 120 (2016) 2751-2760

Physical Chemistry Chemical Physics, 19 (2017) 7947-7954

Physical Chemistry Chemical Physics, 19 (2017) 9584-9591