Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease

Zhiming Wang, Jeremy Rahkola, Jasmina S. Redzic, Ying-Chih Chi, Norman Tran, Todd Holyoak, Hongjin Zheng (), Edward Janoff () and Elan Eisenmesser ()
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Zhiming Wang: University of Colorado Denver, School of Medicine
Jeremy Rahkola: Mucosal and Vaccine Research Program Colorado, Division of Infectious Disease, University of Colorado Denver School of Medicine and Denver Veterans Affairs Medical Center
Jasmina S. Redzic: University of Colorado Denver, School of Medicine
Ying-Chih Chi: Cryo-EM Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center
Norman Tran: University of Waterloo
Todd Holyoak: University of Waterloo
Hongjin Zheng: University of Colorado Denver, School of Medicine
Edward Janoff: Mucosal and Vaccine Research Program Colorado, Division of Infectious Disease, University of Colorado Denver School of Medicine and Denver Veterans Affairs Medical Center
Elan Eisenmesser: University of Colorado Denver, School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract Opportunistic pathogens such as Streptococcus pneumoniae secrete a giant metalloprotease virulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown since their discovery nearly 30 years ago despite the potential for developing vaccines that target these enzymes to block infection. Here we show through a series of cryo-electron microscopy single particle reconstructions how the Streptococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and how this can be inhibited. Specifically, the Streptococcus pneumoniae IgA1 protease subscribes to an active-site-gated mechanism where a domain undergoes a 10.0 Å movement to facilitate cleavage. Monoclonal antibody binding inhibits this conformational change, providing a direct means to block infection at the host interface. These structural studies explain decades of biological and biochemical studies and provides a general strategy to block Streptococcus pneumoniae IgA1 protease activity to potentially prevent infection.

Date: 2020
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DOI: 10.1038/s41467-020-19887-3

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