Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 1, Pages 317-327Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1913690116
Keywords
host-pathogen interaction; pore forming toxins; receptor recognition; leukocidin; integrin
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Funding
- Christian Doppler Laboratory for Knowledge-based Structural Biology and Biotechnology
- Federal Ministry of Economy, Family and Youth through the initiative Laura Bassi Centres of Expertise, funding the Centre of Optimized Structural Studies [253275]
- COST action [BM1405]
- University of Vienna
- iNEXT - Horizon 2020 programme of the European Commission [653706]
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Host-pathogen interactions are central to understanding microbial pathogenesis. The staphylococcal pore-forming cytotoxins hijack important immune molecules but little is known about the underlying molecular mechanisms of cytotoxin-receptor interaction and host specificity. Here we report the structures of a staphylococcal poreforming cytotoxin, leukocidin GH (LukGH), in complex with its receptor (the a-I domain of complement receptor 3, CD11b-I), both for the human and murine homologs. We observe 2 binding interfaces, on the LukG and the LukH protomers, and show that human CD11b-I induces LukGH oligomerization in solution. LukGH binds murine CD11b-I weakly and is inactive toward murine neutrophils. Using a LukGH variant engineered to bind mouse CD11b-I, we demonstrate that cytolytic activity does not only require binding but also receptor-dependent oligomerization. Our studies provide an unprecedented insight into bicomponent leukocidin-host receptor interaction, enabling the development of antitoxin approaches and improved animal models to explore these approaches.
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