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Structural basis for selective AMPylation of Rac-subfamily GTPases by Bartonella effector protein 1 (Bep1)

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Dietz Nikolaus, Huber Markus, Sorg Isabel, Goepfert Arnaud, Harms Alexander, Schirmer Tilman, Dehio Christoph,
Project Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
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Original article (peer-reviewed)

Journal Proceedings of the National Academy of Sciences
Volume (Issue) 118(12)
Page(s) e202324511 - e202324511
Title of proceedings Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2023245118

Open Access

URL http://doi.org/10.1073/pnas.2023245118
Type of Open Access Publisher (Gold Open Access)

Abstract

Small GTPases of the Ras-homology (Rho) family are conserved molecular switches that control fundamental cellular activities in eukaryotic cells. As such, they are targeted by numerous bacterial toxins and effector proteins, which have been intensively investigated regarding their biochemical activities and discrete target spectra; however, the molecular mechanism of target selectivity has remained largely elusive. Here we report a bacterial effector protein that selectively targets members of the Rac subfamily in the Rho family of small GTPases but none in the closely related Cdc42 or RhoA subfamilies. This exquisite target selectivity of the FIC domain AMP-transferase Bep1 from Bartonella rochalimae is based on electrostatic interactions with a subfamily-specific pair of residues in the nucleotide-binding G4 motif and the Rho insert helix. Residue substitutions at the identified positions in Cdc42 enable modification by Bep1, while corresponding Cdc42-like substitutions in Rac1 greatly diminish modification. Our study establishes a structural understanding of target selectivity toward Rac-subfamily GTPases and provides a highly selective tool for their functional analysis.
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