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

TY - JOUR

T1 - Dephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b

AU - Kaspers, Marietta S

AU - Pogenberg, Vivian

AU - Pett, Christian

AU - Ernst, Stefan

AU - Ecker, Felix

AU - Ochtrop, Philipp

AU - Groll, Michael

AU - Hedberg, Christian

AU - Itzen, Aymelt

N1 - © 2023. The Author(s).

PY - 2023/4/19

Y1 - 2023/4/19

N2 - 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.

AB - 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.

KW - Humans

KW - Legionella/metabolism

KW - Phosphorylcholine/metabolism

KW - Legionella pneumophila/metabolism

KW - Legionnaires' Disease

KW - Protein Processing, Post-Translational

KW - Bacterial Proteins/metabolism

KW - rab1 GTP-Binding Proteins/metabolism

U2 - 10.1038/s41467-023-37621-7

DO - 10.1038/s41467-023-37621-7

M3 - SCORING: Journal article

C2 - 37076474

VL - 14

SP - 2245

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

ER -