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.
Highlights
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
The 3D cryo-electron microscopy (cryo-EM) reconstruction of the S. pneumoniae IgA1 protease (IgA1P) resulted in a 3.8 Å resolution map
The overall structure reveals that S. pneumoniae IgA1P is a multi-domain enzyme (Fig. 1d), broadly comprised of N-terminal (NTD; residues 665–1070), middle (MD; 1071–1611), and C-terminal domains (CTD; 1612–1963)
Summary
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. 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. Despite the discovery of the metalloprotease class of bacterial virulence factors 30 years ago[20], their structure and mechanism of substrate engagement has remained unknown until now. We use cryo-electron microscopy (cryo-EM) to elucidate the structure of the S. pneumoniae IgA1P catalytic region alone and in complex with both its IgA1 substrate and a neutralizing monoclonal antibody (mAb), thereby addressing the molecular basis of substrate recognition and enzyme inhibition
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