Crystal Structure of VapBC-1 from Nontypeable Haemophilus influenzae and the Effect of PIN Domain Mutations on Survival during Infection

Molinaro, Ashley L.; Kashipathy, Maithri M.; Lovell, Scott; Battaile, Kevin P.; Coussens, Nathan P.; Shen, Min; Daines, Dayle A.

doi:10.1128/JB.00026-19

Crystal Structure of VapBC-1 from Nontypeable Haemophilus influenzae and the Effect of PIN Domain Mutations on Survival during Infection

Journal Article · Mon Apr 01 04:00:00 EDT 2019 · Journal of Bacteriology

DOI:https://doi.org/10.1128/JB.00026-19· OSTI ID:1526058

Molinaro, Ashley L. ^[1]; Kashipathy, Maithri M. ^[2]; Lovell, Scott ^[2]; Battaile, Kevin P. ^[3]; Coussens, Nathan P. ^[4]; Shen, Min ^[4]; ^[1]

Old Dominion Univ., Norfolk, VA (United States)
Univ. of Kansas, Lawrence, KS (United States)
Hauptman Woodward Medical Research Inst., Argonne, IL (United States)
National Inst. of Health, Rockville, MD (United States). National Center for Advancing Translational Sciences

Toxin-antitoxin (TA) gene pairs have been identified in nearly all bacterial genomes sequenced to date and are thought to facilitate persistence and antibiotic tolerance. TA loci are classified into various types based upon the characteristics of their antitoxins, with those in type II expressing proteic antitoxins. Many toxins from type II modules are ribonucleases that maintain a PilT N-terminal (PIN) domain containing conserved amino acids considered essential for activity. ThevapBC(virulence-associatedprotein) TA system is the largest subfamily in this class and has been linked to pathogenesis of nontypeableHaemophilus influenzae(NTHi). In this study reported here, the crystal structure of the VapBC-1 complex from NTHi was determined to 2.20 Å resolution. Based on this structure, aspartate-to-asparagine and glutamate-to-glutamine mutations of four conserved residues in the PIN domain of the VapC-1 toxin were constructed and the effects of the mutations on protein-protein interactions, growth ofEscherichia coli, and pathogenesisex vivowere tested. Finally, a novel model system was designed and utilized that consists of an NTHi ΔvapBC-1strain complemented inciswith the TA module containing a mutated or wild-type toxin at an ectopic site on the chromosome. This enabled the analysis of the effect of PIN domain toxin mutants in tandem with their wild-type antitoxin under the control of thevapBC-1native promoter and in single copy. This is the first report of a system facilitating the study of TA mutant operons in the background of NTHi during infections of primary human tissuesex vivo.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institute on Deafness and Other Communication Disorders (NIDCD); National Center for Advancing Translational Sciences (NCATS) Division of Pre-Clinical Innovation Intramural Program; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Industrial Macromolecular Crystallography Association; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1526058

Journal Information:: Journal of Bacteriology, Journal Name: Journal of Bacteriology Journal Issue: 12 Vol. 201; ISSN 0021-9193

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
PIN domain
crystal structure
persistence
protein-protein interactions
ribonuclease
toxin-antitoxin

Crystal Structure of VapBC-1 from Nontypeable Haemophilus influenzae and the Effect of PIN Domain Mutations on Survival during Infection

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References (79)

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