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Alpha 5/6 helix domains together with N-terminus determine the apoptotic potency of the Bcl-2 family proteins

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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.

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Abbreviations

Bak:

Bcl-2-antagonist killer

Bax:

Bcl-2-associated X protein

Bcl-2:

B cell lymphoma-2

Bcl-xL:

B-cell lymphoma-extra large

BH domain:

Bcl-2 homology domain

Caspase:

Cysteine aspartase

CCD:

Charge-coupled device

EGFP:

Enhanced green fluorescent protein

EYFP:

Enhanced yellow fluorescent protein

FBS:

Fetal bovine serum

Hr:

Hour

Mcl-1:

Myeloid cell leukaemia sequence 1

MEM:

Minimum essential medium

MOM:

Mitochondrial outer membrane

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

pDNA:

Plasmid DNA

TM:

Transmembrane

UV:

Ultraviolet light

VDAC:

Voltage-dependent anion channel

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Acknowledgments

We want to thank Dr. Y. Tsujimoto for kindly supplying us the pRSET-Bax gene, Dr. Richard J. Youle for providing the YFP-Bak and pEGFP-Bcl-xL genes, Dr. Steven W. Edwards for providing pEGFP-C3-Mcl-1 gene, Dr. Yong Xie for providing Bcl-2 gene, and Dr. L. Scorrano for providing the MEF and MEF-DKO cell lines. This work was supported by grants from the Research Grants Council of Hong Kong (HKUST6466/05 M, N_HKUST616/05 and 660207).

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    Authors and Affiliations

    1. 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

      Kang Xiao

    2. Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China

      Wenrui Zhao, Liying Zhou & Donald Choy Chang

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    1. Kang Xiao
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    Correspondence to Donald Choy Chang.

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    Kang Xiao, Wenrui Zhao have contributed equally to this work.

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    Xiao, K., Zhao, W., Zhou, L. et al. Alpha 5/6 helix domains together with N-terminus determine the apoptotic potency of the Bcl-2 family proteins. Apoptosis 21, 1214–1226 (2016). https://doi.org/10.1007/s10495-016-1283-9

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