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Structural basis of apoptosis inhibition by the Fowlpox virus protein FPV039

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J. Biol. Chem.-2017-Anasir-9010-21.pdfPublished version3.83 MBAdobe PDFView/Open
Title: Structural basis of apoptosis inhibition by the Fowlpox virus protein FPV039
Authors: Anasir, MI
Caria, S
Skinner, MA
Kvansakul, M
Item Type: Journal Article
Abstract: Programmed cell death or apoptosis of infected host cells is an important defense mechanism in response to viral infections. This process is regulated by pro-apoptotic and pro-survival members of the B-cell lymphoma 2 (Bcl-2) protein family. To counter premature death of a virus-infected cell, poxviruses use a range of different molecular strategies, including the mimicry of pro-survival Bcl-2 proteins. One such viral pro-survival protein is the fowlpox virus protein FPV039, which is a potent apoptosis inhibitor, but the precise molecular mechanism by which FPV039 inhibits apoptosis is unknown. To understand how fowlpox virus inhibits apoptosis we examined FPV039 using isothermal titration calorimetry, small-angle X-ray scattering and X-ray crystallography. Here, we report that the fowlpox virus pro-survival protein FPV039 promiscuously binds to cellular pro-apoptotic Bcl-2, and engages all major pro-apoptotic Bcl-2 proteins. Unlike other identified viral Bcl-2 proteins to date, FPV039 engaged with cellular pro-apoptotic Bcl-2 with affinities comparable to those of Bcl-2's endogenous cellular counterparts. Structural studies revealed that FPV039 adopts the conserved Bcl-2 fold observed in cellular pro-survival Bcl-2 proteins, and closely mimics the structure of the pro-survival Bcl-2 family protein Mcl-1. Our findings suggest that FPV039 is a pan Bcl-2 protein inhibitor that can engage all host BH3-only proteins as well as Bcl-2 associated X, apoptosis regulator (Bax) and Bcl-2 antagonist/killer (Bak) proteins to inhibit premature apoptosis of an infected host cell. This work therefore provides a mechanistic platform to better understand FPV039-mediated apoptosis inhibition.
Issue Date: 14-Apr-2017
Date of Acceptance: 14-Apr-2017
URI: http://hdl.handle.net/10044/1/48140
DOI: https://dx.doi.org/10.1074/jbc.M116.768879
ISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology
Start Page: 9010
End Page: 9021
Journal / Book Title: Journal of Biological Chemistry
Volume: 292
Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. This research was originally published in Journal of Biological Chemistry.
Sponsor/Funder: Biotechnology and Biological Sciences Research Council (BBSRC)
Funder's Grant Number: BB/K002465/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
PROGRAMMED CELL-DEATH
BCL-2 FAMILY
PHYLOGENETIC ANALYSIS
BH3-ONLY PROTEINS
PROSURVIVAL BCL-2
INFECTED-CELLS
VIRAL HOMOLOG
BH3 DOMAIN
F1L
ENCODES
B-cell lymphoma 2 (Bcl-2) family
X-ray crystallography
apoptosis
isothermal titration calorimetry (ITC)
poxvirus
small-angle X-ray scattering (SAXS)
Animals
Apoptosis Regulatory Proteins
Avian Proteins
Chickens
Crystallography, X-Ray
Fowlpox virus
Humans
Myeloid Cell Leukemia Sequence 1 Protein
Protein Domains
Viral Proteins
bcl-2-Associated X Protein
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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