title: Alpha 5/6 helix domains together with N-terminus determine the apoptotic potency of the Bcl-2 family proteins.
abstract: A critical process in apoptosis is the permeabilization of the mitochondrial outer membrane (MOM). This process is known to be regulated by the multi-domain Bcl-2 family proteins. For example, the pro-apoptotic proteins Bax and Bak are responsible for forming pores at MOM. The anti-apoptotic proteins (including Bcl-2, Mcl-1 and Bcl-xL), on the other hand, can inhibit this pore-forming process. Interestingly, although these two subgroups of proteins perform opposite apoptotic functions, their structures are very similar. This raises two highly interesting questions: (1) Why do these structurally similar proteins play opposite roles in apoptosis? (2) What are the roles of different functional domains of a Bcl-2 family protein in determining its apoptotic property? In this study, we generated a series of deletion mutants and substitution chimera, and used a combination of molecular biology, bio-informatics and living cell imaging techniques to answer these questions. Our major findings are: (1) All of the Bcl-2 family proteins appear to possess an intrinsic pro-apoptotic property. (2) The N-termini of these proteins play an active role in suppressing their pro-apoptotic function. (3) The apoptotic potency is positively correlated with membrane affinity of the alpha 5/6 helix domains. (4) Charge distribution flanking the alpha 5/6 helices is also important for the apoptotic potency. These findings explain why different members of Bcl-2 family proteins with similar domain composition can function oppositely in the apoptotic process.
authors.affiliation: Shenzhen Key Laboratory of Marine Bioresource and Eco-environmental Science, Guangdong Engineering Research; Center for Marine Algal Biotechnology, College of Life Science and Oceanography; Key Laboratory of Optoeletronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoeletronic Engineering, Shenzhen University, 518060, Shenzhen, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Wenrui
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. bochang@ust.hk.
authors.forename: Donald Choy
authors.initials: DC
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D006801:Humans; D051379:Mice; D005810:Multigene Family; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
keywords: Apoptosis; Bcl-2 family proteins; Membrane affinity; The N-terminus; The alpha 5/6 helices