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Structural insights into the activation mechanism of antimicrobial GBP1

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Item Type:Article
Title:Structural insights into the activation mechanism of antimicrobial GBP1
Creators Name:Weismehl, M. and Chu, X. and Kutsch, M. and Lauterjung, P. and Herrmann, C. and Kudryashev, M. and Daumke, O.
Abstract:The dynamin-related human guanylate-binding protein 1 (GBP1) mediates host defenses 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 soluble and membrane-bound GBP1 oligomers, which show that GBP1 assembles in an outstretched dimeric conformation. We identify a surface-exposed helix in the large GTPase domain that contributes to the oligomerization interface, and we probe its nucleotide- and dimerization-dependent movements that facilitate 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 within an antimicrobial protein coat.
Keywords:Dynamin Superfamily, Electron Microscopy, Guanylate-Binding Proteins, GTPase, Oligomerization
Source:EMBO Journal
Publisher:Springer Nature
Page Range:615-636
Date:15 February 2024
Official Publication:https://doi.org/10.1038/s44318-023-00023-y
PubMed:View item in PubMed

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