Structural insights into the activation mechanism of antimicrobial GBP1

Autor/innen

  • M. Weismehl
  • X. Chu
  • M. Kutsch
  • P. Lauterjung
  • C. Herrmann
  • M. Kudryashev
  • O. Daumke

Journal

  • EMBO Journal

Quellenangabe

  • EMBO J 43 (4): 615-636

Zusammenfassung

  • 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.


DOI

doi:10.1038/s44318-023-00023-y