The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core

Abstract

BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.

Apoptosis and its therapeutic implications in neurodegenerative diseases

“…Additionally, Bcl‐2 family members regulate the permeability transition (PT)‐pore during apoptosis (Bloch et al, 2021; Morris et al, 2021). For instance, BAX is conformationally altered, and it consequently inserts itself into the outer mitochondrial membrane opening mitochondrial PT‐pore (Bloch et al, 2021; Pena‐Blanco & Garcia‐Saez, 2018; Rathore et al, 2017). Thus, the PT‐pore connecting the inner and outer mitochondrial membranes is opened causing depolarization of the mitochondria, release of small molecules into the cytosol, and enlarged mitochondrial osmosis with subsequent rupture of the outer mitochondrial membrane (Rathore et al, 2017).…”

“…Similarly, BH3‐only Bcl‐2 members need multidomain Bcl‐2 members to trigger apoptosis (Renault et al, 2014). Indeed, binding of BH3‐only members with multidomain members is very essential for inducing apoptosis by stimulating structural alterations and other events that ultimately lead to the permeabilization of the outer mitochondrial membrane (Bloch et al, 2021; Rose et al, 2021). On the other hand, pro‐apoptotic BH3‐only members, such as p53 upregulated modulator of apoptosis (PUMA), bind anti‐apoptotic Bcl‐2 proteins neutralizing them and subsequently inducing apoptosis (Chen et al, 2018; Vavrova & Rezacova, 2014).…”

“…On the other hand, pro‐apoptotic BH3‐only members, such as p53 upregulated modulator of apoptosis (PUMA), bind anti‐apoptotic Bcl‐2 proteins neutralizing them and subsequently inducing apoptosis (Chen et al, 2018; Vavrova & Rezacova, 2014). Additionally, Bcl‐2 family members regulate the permeability transition (PT)‐pore during apoptosis (Bloch et al, 2021; Morris et al, 2021). For instance, BAX is conformationally altered, and it consequently inserts itself into the outer mitochondrial membrane opening mitochondrial PT‐pore (Bloch et al, 2021; Pena‐Blanco & Garcia‐Saez, 2018; Rathore et al, 2017).…”

Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency

“…2c, d ). To probe the membrane selectivity of VLCAD for cardiolipin-enriched liposomes reflective of the inner mitochondrial membrane (80% PC, 20% CL) 24 , we repeated the translocation experiment with liposomes that instead mimic the membrane composition of the outer mitochondrial membrane (48% PC, 28% phosphatidylethanolamine, 10% phosphatidylinositol, 10% phosphatidylserine, and 4% CL) 26 , 27 and observed little to no translocation (Supplementary Fig. 2e, f ).…”

Expanding the Biological Importance of Protein Structures: Insight into Dynamic Biological Function from Protein Folding Theory Analyses

“…Consistent with this observation is the large number of hydrophobic contacts in regions I, II, and III confer thermodynamic stability to Bax. In addition, a study investigating the stable interior of Bax found that residues 113–116 are responsible maintaining the integrity of the protein . Indeed, contacts with these residues can be found in region II in Figure B.…”