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Single Amino Acid Replacements in RocA Disrupt Protein-Protein Interactions To Alter the Molecular Pathogenesis of Group A Streptococcus.

Authors
  • Bernard, Paul E1, 2
  • Duarte, Amey1
  • Bogdanov, Mikhail3
  • Musser, James M1, 4
  • Olsen, Randall J5, 2, 4
  • 1 Center for Molecular and Translational Human Infectious Disease Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas, USA.
  • 2 Texas A&M Health Science Center College of Medicine, Bryan, Texas, USA.
  • 3 Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas, USA.
  • 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, USA.
  • 5 Center for Molecular and Translational Human Infectious Disease Research, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas, USA [email protected]
Type
Published Article
Journal
Infection and Immunity
Publisher
American Society for Microbiology
Publication Date
Oct 19, 2020
Volume
88
Issue
11
Identifiers
DOI: 10.1128/IAI.00386-20
PMID: 32817331
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Group A Streptococcus (GAS) is a human-specific pathogen and major cause of disease worldwide. The molecular pathogenesis of GAS, like many pathogens, is dependent on the coordinated expression of genes encoding different virulence factors. The control of virulence regulator/sensor (CovRS) two-component system is a major virulence regulator of GAS that has been extensively studied. More recent investigations have also involved regulator of Cov (RocA), a regulatory accessory protein to CovRS. RocA interacts, in some manner, with CovRS; however, the precise molecular mechanism is unknown. Here, we demonstrate that RocA is a membrane protein containing seven transmembrane helices with an extracytoplasmically located N terminus and cytoplasmically located C terminus. For the first time, we demonstrate that RocA directly interacts with itself (RocA) and CovS, but not CovR, in intact cells. Single amino acid replacements along the entire length of RocA disrupt RocA-RocA and RocA-CovS interactions to significantly alter the GAS virulence phenotype as defined by secreted virulence factor activity in vitro and tissue destruction and mortality in vivo In summary, we show that single amino acid replacements in a regulatory accessory protein can affect protein-protein interactions to significantly alter the virulence of a major human pathogen. Copyright © 2020 American Society for Microbiology.

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