The Chlamydia pneumoniae effector SemD exploits its host’s endocytic machinery by structural and functional mimicry

Fabienne Kocher, Violetta Applegate, Jens Reiners, Astrid Port, Dominik Spona, Sebastian Hänsch, Amin Mirzaiebadizi, Mohammad Reza Ahmadian, Sander H. J. Smits, Johannes H. Hegemann () and Katja Mölleken
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Fabienne Kocher: Faculty of Mathematics and Natural Sciences, Institute for Functional Microbial Genomics
Violetta Applegate: Center for Structural Studies
Jens Reiners: Center for Structural Studies
Astrid Port: Center for Structural Studies
Dominik Spona: Faculty of Mathematics and Natural Sciences, Institute for Functional Microbial Genomics
Sebastian Hänsch: Center for Advanced Imaging
Amin Mirzaiebadizi: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Mohammad Reza Ahmadian: Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf
Sander H. J. Smits: Center for Structural Studies
Johannes H. Hegemann: Faculty of Mathematics and Natural Sciences, Institute for Functional Microbial Genomics
Katja Mölleken: Faculty of Mathematics and Natural Sciences, Institute for Functional Microbial Genomics

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract To enter epithelial cells, the obligate intracellular pathogen Chlamydia pneumoniae secretes early effector proteins, which bind to and modulate the host-cell’s plasma membrane and recruit several pivotal endocytic host proteins. Here, we present the high-resolution structure of an entry-related chlamydial effector protein, SemD. Co-crystallisation of SemD with its host binding partners demonstrates that SemD co-opts the Cdc42 binding site to activate the actin cytoskeleton regulator N-WASP, making active, GTP-bound Cdc42 superfluous. While SemD binds N-WASP much more strongly than Cdc42 does, it does not bind the Cdc42 effector protein FMNL2, indicating effector protein specificity. Furthermore, by identifying flexible and structured domains, we show that SemD can simultaneously interact with the membrane, the endocytic protein SNX9, and N-WASP. Here, we show at the structural level how a single effector protein can hijack central components of the host’s endocytic system for efficient internalization.

Date: 2024
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DOI: 10.1038/s41467-024-51681-3

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