The structure of Streptococcus pneumoniae IgA1 Protease in complex with its IgA1 substrate.
EMSL Project ID
51575
Abstract
We propose completing the first complex of a bacterial IgA1 Protease (IgA1P) in complex with its human IgA1 substrate. Many opportunistic bacteria produce an IgA1P to cleave their human host IgA1 within its hinge region (Fig.1), the linker that connects the FAB to the Fc, thereby blocking the initial immune response, which includes Streptococcus pneumoniae (SPN). The World Health Organization declares SPN a “major global public health problem” due to an alarming increase in non-vaccine serotypes, prompting the immediate need to develop universal vaccines. SPN along with several opportunistic bacteria produce a unique type of IgA1P that is a giant metalloprotease. Thus, the potential for developing vaccines by utilizing immunogenic regions of this SPN IgA1P has been advocated; however, no studies have elucidated the structure of Streptococcus pneumoniae IgA1P either alone or in complex with its IgA1 substrate. While we have recently determined the high-resolution structure of the SPN IgA1P alone and in complex with a neutralizing mAb through our previously awarded time, here we aim to complete data collection in order to elucidate the structure of the FIRST IgA1P/IgA1 complex. To this end, we have produced an active site mutant of IgA1P that is catalytically impaired but not completely dead at the stoichiometric concentrations needed for structural elucidation. A low-resolution structure of this SPN IgA1P/IgA1 complex was calculated and already provides for a fundamental understanding of the conformational changes necessary for substrate engagement but does require further data collection to produce a high-resolution structure and elucidate the specific interdomain and intermolecular contacts. Considering the preliminary data provided below, we believe that the following goal is completely feasible and that this goal will address our hypothesis provided as well.
Project Details
Start Date
2020-07-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members