Abstract
Bax∆2 is a pro-apoptotic anti-tumor protein in the Bax family. While most of the Bax family causes cell death by targeting mitochondria, Bax∆2 forms cytosolic aggregates and activates caspase 8-dependent cell death. We previously showed that the Bax∆2 helix α9 is critical for caspase 8 recruitment. However, the interaction between these two proteins at the structural level is unknown. In this in silico study, we performed molecular dynamics (MD) simulations and protein–protein docking on Bax∆2 variants. The results suggest that the Bax∆2 variants have different stable states. Mutating the Baxα mitochondria-targeting signal [L26P/L27P] appears to introduce a kink into helix α1. Protein–protein docking suggests that helices α9 of both wild-type Bax∆2 and Bax∆2 caspase 8 binding-deficient mutant [L164P] can fit in the same caspase 8 binding site, but the mutant is unable to fit as well as wild-type Bax∆2. Together, these data point to a structural basis for explaining Bax∆2 function in caspase 8-dependent cell death.
Highlights
Programmed cell death, called apoptosis, plays a fundamental role in both physiological and pathological processes such as development, tumorigenesis and neurodegeneration [1,2]
We have developed a structural model for the role of Bax∆2 function in caspase 8-dependent cell death
Structures of Bax variants predicted by the RaptorX server were all very similar to one another; this result is probably due to the models being based on the same templates
Summary
Programmed cell death, called apoptosis, plays a fundamental role in both physiological and pathological processes such as development, tumorigenesis and neurodegeneration [1,2]. The intrinsic pathway is triggered by a death insult, such as a chemo-drug, radiation, or intracellular stress In this pathway, cytosolic Bax monomers oligomerize and form ring-like structures on mitochondria. In addition to its potential benefits in cancer treatment, Bax∆2 is compelling because, unlike its relatives in the Bax family, it is not involved in the intrinsic apoptotic pathway, but activates the extrinsic pathway [20,21,22]. A point-mutation in helix α9, L164P, significantly impairs the ability of Bax∆2 to recruit caspase 8 for cell death [21]. We performed protein–protein docking to estimate the binding affinities between Bax∆2 and caspase 8 DED Based on these calculations, we have developed a structural model for the role of Bax∆2 function in caspase 8-dependent cell death. Instt.rJu. cMtuolr. aSlcim. 20o2d0,e2l1f,o5r47t6he role of Bax∆2 function in caspase 8-dependent cell death
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