An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates



Robert G. Hawley*, 1, Yuzhong Chen, 2, Irene Riz1, Chen Zeng2
1 Department of Anatomy and Regenerative Biology, The George Washington University, Washington, DC 20037, USA
2 Department of Physics, The George Washington University, Washington, DC 20052, USA


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© 2010 Hawley et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Department of Anatomy and Regenerative Biology, George Washington University, 2300 I Street NW, Washington, DC 20037, USA; Tel: 202-994-3511; Fax: 202-994-8885; E-mail: rghawley@gwu.edu
Current address: Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, AZ 85287, USA


Abstract

In this study, we utilized an integrated bioinformatics and computational biology approach in search of new BH3-only proteins belonging to the BCL2 family of apoptotic regulators. The BH3 (BCL2 homology 3) domain mediates specific binding interactions among various BCL2 family members. It is composed of an amphipathic α-helical region of approximately 13 residues that has only a few amino acids that are highly conserved across all members. Using a generalized motif, we performed a genome-wide search for novel BH3-containing proteins in the NCBI Consensus Coding Sequence (CCDS) database. In addition to known pro-apoptotic BH3-only proteins, 197 proteins were recovered that satisfied the search criteria. These were categorized according to α-helical content and predictive binding to BCL-xL (encoded by BCL2L1) and MCL-1, two representative anti-apoptotic BCL2 family members, using position-specific scoring matrix models. Notably, the list is enriched for proteins associated with autophagy as well as a broad spectrum of cellular stress responses such as endoplasmic reticulum stress, oxidative stress, antiviral defense, and the DNA damage response. Several potential novel BH3-containing proteins are highlighted. In particular, the analysis strongly suggests that the apoptosis inhibitor and DNA damage response regulator, AVEN, which was originally isolated as a BCL-xLinteracting protein, is a functional BH3-only protein representing a distinct subclass of BCL2 family members.

Keywords: Apoptosis, autophagy, DNA damage checkpoint.