Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab1
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Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab1. / Du, Jiqing; Wrisberg, Marie-Kristin von; Gulen, Burak; Stahl, Matthias; Pett, Christian; Hedberg, Christian; Lang, Kathrin; Schneider, Sabine; Itzen, Aymelt.
in: NAT COMMUN, Jahrgang 12, Nr. 1, 460, 19.01.2021.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab1
AU - Du, Jiqing
AU - Wrisberg, Marie-Kristin von
AU - Gulen, Burak
AU - Stahl, Matthias
AU - Pett, Christian
AU - Hedberg, Christian
AU - Lang, Kathrin
AU - Schneider, Sabine
AU - Itzen, Aymelt
PY - 2021/1/19
Y1 - 2021/1/19
N2 - Legionella pneumophila infects eukaryotic cells by forming a replicative organelle - the Legionella containing vacuole. During this process, the bacterial protein DrrA/SidM is secreted and manipulates the activity and post-translational modification (PTM) states of the vesicular trafficking regulator Rab1. As a result, Rab1 is modified with an adenosine monophosphate (AMP), and this process is referred to as AMPylation. Here, we use a chemical approach to stabilise low-affinity Rab:DrrA complexes in a site-specific manner to gain insight into the molecular basis of the interaction between the Rab protein and the AMPylation domain of DrrA. The crystal structure of the Rab:DrrA complex reveals a previously unknown non-conventional Rab-binding site (NC-RBS). Biochemical characterisation demonstrates allosteric stimulation of the AMPylation activity of DrrA via Rab binding to the NC-RBS. We speculate that allosteric control of DrrA could in principle prevent random and potentially cytotoxic AMPylation in the host, thereby perhaps ensuring efficient infection by Legionella.
AB - Legionella pneumophila infects eukaryotic cells by forming a replicative organelle - the Legionella containing vacuole. During this process, the bacterial protein DrrA/SidM is secreted and manipulates the activity and post-translational modification (PTM) states of the vesicular trafficking regulator Rab1. As a result, Rab1 is modified with an adenosine monophosphate (AMP), and this process is referred to as AMPylation. Here, we use a chemical approach to stabilise low-affinity Rab:DrrA complexes in a site-specific manner to gain insight into the molecular basis of the interaction between the Rab protein and the AMPylation domain of DrrA. The crystal structure of the Rab:DrrA complex reveals a previously unknown non-conventional Rab-binding site (NC-RBS). Biochemical characterisation demonstrates allosteric stimulation of the AMPylation activity of DrrA via Rab binding to the NC-RBS. We speculate that allosteric control of DrrA could in principle prevent random and potentially cytotoxic AMPylation in the host, thereby perhaps ensuring efficient infection by Legionella.
KW - Adenosine Monophosphate/metabolism
KW - Allosteric Regulation
KW - Bacterial Proteins/genetics
KW - Binding Sites/genetics
KW - Crystallography, X-Ray
KW - Guanine Nucleotide Exchange Factors/genetics
KW - Guanosine Triphosphate/metabolism
KW - Humans
KW - Legionella pneumophila/metabolism
KW - Legionnaires' Disease/microbiology
KW - Macrophages, Alveolar/metabolism
KW - Phagocytosis
KW - Protein Binding
KW - Protein Processing, Post-Translational
KW - Recombinant Proteins/genetics
KW - rab1 GTP-Binding Proteins/genetics
U2 - 10.1038/s41467-020-20702-2
DO - 10.1038/s41467-020-20702-2
M3 - SCORING: Journal article
C2 - 33469029
VL - 12
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
M1 - 460
ER -