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Structural requirements for membrane binding of human guanylate-binding protein 1.

Publication ,  Journal Article
Sistemich, L; Dimitrov Stanchev, L; Kutsch, M; Roux, A; Günther Pomorski, T; Herrmann, C
Published in: The Febs Journal
July 2021

Human guanylate-binding protein 1 (hGBP1) is a key player in innate immunity and fights diverse intracellular microbial pathogens. Its antimicrobial functions depend on hGBP1's GTP binding- and hydrolysis-induced abilities to form large, structured polymers and to attach to lipid membranes. Crucial for both of these biochemical features is the nucleotide-controlled release of the C terminally located farnesyl moiety. Here, we address molecular details of the hGBP1 membrane binding mechanism by employing recombinant, fluorescently labeled hGBP1, and artificial membranes. We demonstrate the importance of the GTPase activity and the resulting structural rearrangement of the hGBP1 molecule, which we term the open state. This open state is supported and stabilized by homodimer contacts involving the middle domain of the protein and is further stabilized by binding to the lipid bilayer surface. We show that on the surface of the lipid bilayer a hGBP1 monolayer is built in a pins in a pincushion-like arrangement with the farnesyl tail integrated in the membrane and the N-terminal GTPase domain facing outwards. We suggest that similar intramolecular contacts between neighboring hGBP1 molecules are responsible for both polymer formation and monolayer formation on lipid membranes. Finally, we show that tethering of large unilamellar vesicles occurs after the vesicle surface is fully covered by the monolayer. Both hGBP1 polymer formation and hGBP1-induced vesicle tethering have implications for understanding the molecular mechanism of combating bacterial pathogens. DATABASES: Structural data are available in RCSB Protein Data Bank under the accession numbers: 6K1Z, 2D4H.

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Published In

The Febs Journal

DOI

EISSN

1742-4658

ISSN

1742-464X

Publication Date

July 2021

Volume

288

Issue

13

Start / End Page

4098 / 4114

Related Subject Headings

  • Protein Multimerization
  • Protein Domains
  • Protein Binding
  • Lipid Bilayers
  • Kinetics
  • Hydrolysis
  • Humans
  • Guanosine Triphosphate
  • GTP-Binding Proteins
  • GTP Phosphohydrolases
 

Citation

APA
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Sistemich, L., Dimitrov Stanchev, L., Kutsch, M., Roux, A., Günther Pomorski, T., & Herrmann, C. (2021). Structural requirements for membrane binding of human guanylate-binding protein 1. The Febs Journal, 288(13), 4098–4114. https://doi.org/10.1111/febs.15703
Sistemich, Linda, Lyubomir Dimitrov Stanchev, Miriam Kutsch, Aurélien Roux, Thomas Günther Pomorski, and Christian Herrmann. “Structural requirements for membrane binding of human guanylate-binding protein 1.The Febs Journal 288, no. 13 (July 2021): 4098–4114. https://doi.org/10.1111/febs.15703.
Sistemich L, Dimitrov Stanchev L, Kutsch M, Roux A, Günther Pomorski T, Herrmann C. Structural requirements for membrane binding of human guanylate-binding protein 1. The Febs Journal. 2021 Jul;288(13):4098–114.
Sistemich, Linda, et al. “Structural requirements for membrane binding of human guanylate-binding protein 1.The Febs Journal, vol. 288, no. 13, July 2021, pp. 4098–114. Epmc, doi:10.1111/febs.15703.
Sistemich L, Dimitrov Stanchev L, Kutsch M, Roux A, Günther Pomorski T, Herrmann C. Structural requirements for membrane binding of human guanylate-binding protein 1. The Febs Journal. 2021 Jul;288(13):4098–4114.
Journal cover image

Published In

The Febs Journal

DOI

EISSN

1742-4658

ISSN

1742-464X

Publication Date

July 2021

Volume

288

Issue

13

Start / End Page

4098 / 4114

Related Subject Headings

  • Protein Multimerization
  • Protein Domains
  • Protein Binding
  • Lipid Bilayers
  • Kinetics
  • Hydrolysis
  • Humans
  • Guanosine Triphosphate
  • GTP-Binding Proteins
  • GTP Phosphohydrolases