Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by...Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.展开更多
Bcl-2 family proteins(BFPs)are essential regulators of regulated cell death(RCD),and their dysregulation is implicated in a wide range of disorders,including cancer,neurodegenerative diseases,and autoimmune conditions...Bcl-2 family proteins(BFPs)are essential regulators of regulated cell death(RCD),and their dysregulation is implicated in a wide range of disorders,including cancer,neurodegenerative diseases,and autoimmune conditions.Recent studies have shown that BFPs also play critical roles in autophagy,calcium homeostasis,neuronal function,and mitochondrial dynamics,underscoring their multifaceted contributions to cellular health.In this review,we summarize the current knowledge concerning the physiological roles and structural diversity of BFPs,with a particular focus on key multidomain proteins such as Bak,Bax,and Bok.Our findings highlight persistent challenges and knowledge gaps,especially concerning the interactions between BFPs and diverse cellular pathways.In conclusion,BFPs act as fundamental regulators of cell survival and apoptosis.While significant progress has been made in elucidating their molecular mechanisms,important questions remain—particularly regarding the precise structural dynamics of pore formation,the influence of the mitochondrial lipid composition,and the balance between pro-and anti-apoptotic members.Finally,the therapeutic potential of BFP-targeted drugs,including BH3 mimetics,offers promising avenues for treating cancer and other diseases characterized by aberrant regulation of apoptosis.展开更多
文摘Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles： the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.
文摘Bcl-2 family proteins(BFPs)are essential regulators of regulated cell death(RCD),and their dysregulation is implicated in a wide range of disorders,including cancer,neurodegenerative diseases,and autoimmune conditions.Recent studies have shown that BFPs also play critical roles in autophagy,calcium homeostasis,neuronal function,and mitochondrial dynamics,underscoring their multifaceted contributions to cellular health.In this review,we summarize the current knowledge concerning the physiological roles and structural diversity of BFPs,with a particular focus on key multidomain proteins such as Bak,Bax,and Bok.Our findings highlight persistent challenges and knowledge gaps,especially concerning the interactions between BFPs and diverse cellular pathways.In conclusion,BFPs act as fundamental regulators of cell survival and apoptosis.While significant progress has been made in elucidating their molecular mechanisms,important questions remain—particularly regarding the precise structural dynamics of pore formation,the influence of the mitochondrial lipid composition,and the balance between pro-and anti-apoptotic members.Finally,the therapeutic potential of BFP-targeted drugs,including BH3 mimetics,offers promising avenues for treating cancer and other diseases characterized by aberrant regulation of apoptosis.
