Variola virus F1L is a Bcl-2-like protein that unlike its vaccinia virus counterpart inhibits apoptosis independent of Bim

Cell Death & Disease
B MarshallM Kvansakul

Abstract

Subversion of host cell apoptosis is an important survival strategy for viruses to ensure their own proliferation and survival. Certain viruses express proteins homologous in sequence, structure and function to mammalian pro-survival B-cell lymphoma 2 (Bcl-2) proteins, which prevent rapid clearance of infected host cells. In vaccinia virus (VV), the virulence factor F1L was shown to be a potent inhibitor of apoptosis that functions primarily be engaging pro-apoptotic Bim. Variola virus (VAR), the causative agent of smallpox, harbors a homolog of F1L of unknown function. We show that VAR F1L is a potent inhibitor of apoptosis, and unlike all other characterized anti-apoptotic Bcl-2 family members lacks affinity for the Bim Bcl-2 homology 3 (BH3) domain. Instead, VAR F1L engages Bid BH3 as well as Bak and Bax BH3 domains. Unlike its VV homolog, variola F1L only protects against Bax-mediated apoptosis in cellular assays. Crystal structures of variola F1L bound to Bid and Bak BH3 domains reveal that variola F1L forms a domain-swapped Bcl-2 fold, which accommodates Bid and Bak BH3 in the canonical Bcl-2-binding groove, in a manner similar to VV F1L. Despite the observed conservation of structure and sequence, variola F1L inhibits ap...Continue Reading

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Citations

Oct 5, 2016·Immunologic Research·Gaurav ShrivastavaLeticia Cedillo-Barrón
Apr 16, 2017·The Journal of Biological Chemistry·Mohd Ishtiaq AnasirMarc Kvansakul
Oct 7, 2017·Viruses·Marc KvansakulMark G Hinds
Aug 9, 2017·Viruses·Daniel Brian NicholsJessica Cottrell
Feb 28, 2018·The Journal of Biological Chemistry·Suresh BanjaraMarc Kvansakul
Jan 6, 2017·Journal of Virology·Suresh BanjaraMarc Kvansakul
Oct 7, 2017·Current Medicinal Chemistry·Giulia FreerMauro Pistello
May 16, 2020·The FEBS Journal·Chathura D SuraweeraMarc Kvansakul
Aug 11, 2020·The Biochemical Journal·Suresh BanjaraMarc Kvansakul
Jan 17, 2020·Biomolecules·Suresh BanjaraMarc Kvansakul
Aug 8, 2015·Acta Crystallographica. Section D, Biological Crystallography·Denis R BurtonMarc Kvansakul
Nov 12, 2020·The Biochemical Journal·Chathura D SuraweeraMarc Kvansakul
Dec 31, 2020·Pathogens·Chathura D SuraweeraMarc Kvansakul

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Methods Mentioned

BETA
PCR
gel-filtration
flow cytometry

Software Mentioned

CCP4
Phenix
XDS
PHASER

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