Kalvis Brangulis, Valerie Sürth, Ashley L Marcinkiewicz, Inara Akopjana, Andris Kazaks, Janis Bogans, Alisa Huber, Yi-Pin Lin, Peter Kraiczy
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CspZ variant-specific interaction with Factor H incorporates a metal site to support Lyme borreliae complement evasion.
Polymorphic microbial immune evasion proteins dictate the pathogen species- or strain-specific virulence. Metals can impact how microbial proteins confer host-pathogen interactions, but whether this activity can be allelically variable is unclear. Here, we investigate the polymorphic CspZ protein of Lyme disease (LD) spirochete bacteria to assess the role of metals in protein-protein interaction. CspZ facilitates evasion of the complement system, the first-line of immune defense through binding to the complement regulator Factor H (FH). By obtaining a high-resolution co-crystal CspZ-FH structure, we identified a zinc coordinating the binding of FH SCR6-7 domains to a Glu65 on a loop from CspZ of B. burgdorferi B31. However, zinc is dispensable for human FH binding for CspZ orthologs with a different loop orientation and/or lacking this glutamate. Phylogenetic analysis of all known human FH binding CspZ variants further grouped the proteins into three unique lineages correlating with loop sequences. This suggests multiple FH-binding mechanisms evolved through LD spirochete-host interactions. Overall, this multidisciplinary work elucidates how the allelically-specific immune evasion role of metals is impacted by microbial protein polymorphisms.
期刊介绍:
The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.