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Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease

Zhiming Wang1, Jeremy Rahkola2, Jasmina S Redzic1

  • 1Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, School of Medicine, Aurora, CO, 80045, USA.

Nature Communications
|November 28, 2020
PubMed

Insights

Researchers revealed how Streptococcus pneumoniae IgA1 protease cleaves host IgA1 using cryo-electron microscopy. Monoclonal antibodies can block this mechanism, offering a potential strategy to prevent infections caused by this opportunistic pathogen.

Area of Science:

  • Microbiology
  • Structural Biology
  • Immunology

Background:

  • * Streptococcus pneumoniae is an opportunistic pathogen that causes infections by secreting a metalloprotease virulence factor.
  • * This protease cleaves human immunoglobulin A1 (IgA1), a key component of the mucosal immune system.
  • * The molecular mechanism of IgA1 cleavage by this protease has remained elusive for nearly 30 years.

Purpose of the Study:

  • * To elucidate the molecular mechanism by which Streptococcus pneumoniae IgA1 protease cleaves its IgA1 substrate.
  • * To identify potential strategies for inhibiting the protease activity to prevent infections.

Main Methods:

  • * Cryo-electron microscopy (cryo-EM) single particle reconstructions were employed.
  • * Structural analysis was performed to understand enzyme-substrate interactions and conformational changes.
  • * The effect of monoclonal antibody binding on protease activity was investigated.

Main Results:

  • * The study reveals an active-site-gated mechanism for IgA1 cleavage, involving a domain movement of 10.0 Å.
  • * Structural data demonstrates how the protease recognizes and binds its IgA1 substrate.
  • * Monoclonal antibody binding was shown to inhibit the conformational change essential for cleavage.

Conclusions:

  • * The structural insights explain long-standing biological and biochemical observations regarding IgA1 protease function.
  • * Inhibiting the conformational change through antibody binding offers a direct strategy to block protease activity.
  • * This research provides a generalizable approach for developing therapeutics targeting Streptococcus pneumoniae infections.

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