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bioRxiv · 10.1101/2023.08.01.551421

Elucidating the activation mechanism for GBP1 oligomerization

Daumke, O.·Weismehl, M.·Chu, X.·Kutsch, M.·Lauterjung, P.·Herrmann, C.·Kudryashev, M.
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Abstract

The dynamin-related human guanylate-binding protein 1 (GBP1) mediates host defense against microbial pathogens. Upon GTP binding and hydrolysis, auto-inhibited GBP1 monomers dimerize and assemble into soluble and membrane-bound oligomers, which are crucial for innate immune responses. How higher-order GBP1 oligomers are built from dimers and how assembly is coordinated with nucleotide-dependent conformational changes has remained elusive. Here, we present cryo-electron microscopy-based structural data of the soluble and membrane-bound GBP1 oligomers demonstrating that GBP1 assembles in an outstretched dimeric conformation. We identify a surface-exposed helix in the large GTPase domain, which contributes to the oligomerization interface, and probe its nucleotide- and dimerization-dependent movements facilitating the formation of an antimicrobial protein coat on a Gram-negative bacterial pathogen. Our results reveal a sophisticated activation mechanism for GBP1 in which nucleotide-dependent structural changes coordinate dimerization, oligomerization, and membrane binding to allow encapsulation of pathogens with an antimicrobial protein coat.

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Daumke, O., Weismehl, M., Chu, X., Kutsch, M., Lauterjung, P., Herrmann, C., Kudryashev, M.. 2023-08-03. Elucidating the activation mechanism for GBP1 oligomerization. https://doi.org/10.1101/2023.08.01.551421

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