Dephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b

Marietta S. Kaspers, Vivian Pogenberg, Christian Pett, Stefan Ernst, Felix Ecker, Philipp Ochtrop, Michael Groll, Christian Hedberg and Aymelt Itzen ()
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Marietta S. Kaspers: University Medical Centre Hamburg-Eppendorf (UKE)
Vivian Pogenberg: University Medical Centre Hamburg-Eppendorf (UKE)
Christian Pett: Umeå University
Stefan Ernst: Technical University of Munich
Felix Ecker: Technical University of Munich
Philipp Ochtrop: Umeå University
Michael Groll: Technical University of Munich
Christian Hedberg: Umeå University
Aymelt Itzen: University Medical Centre Hamburg-Eppendorf (UKE)

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Bacterial pathogens often make use of post-translational modifications to manipulate host cells. Legionella pneumophila, the causative agent of Legionnaires disease, secretes the enzyme AnkX that uses cytidine diphosphate-choline to post-translationally modify the human small G-Protein Rab1 with a phosphocholine moiety at Ser76. Later in the infection, the Legionella enzyme Lem3 acts as a dephosphocholinase, hydrolytically removing the phosphocholine. While the molecular mechanism for Rab1 phosphocholination by AnkX has recently been resolved, structural insights into the activity of Lem3 remained elusive. Here, we stabilise the transient Lem3:Rab1b complex by substrate mediated covalent capture. Through crystal structures of Lem3 in the apo form and in complex with Rab1b, we reveal Lem3’s catalytic mechanism, showing that it acts on Rab1 by locally unfolding it. Since Lem3 shares high structural similarity with metal-dependent protein phosphatases, our Lem3:Rab1b complex structure also sheds light on how these phosphatases recognise protein substrates.

Date: 2023
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DOI: 10.1038/s41467-023-37621-7

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