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Barthelmes, K. ; Ramcke, E.* ; Kang, H.-S. ; Sattler, M. ; Itzen, A.*

Conformational control of small GTPases by AMPylation.

Proc. Natl. Acad. Sci. U.S.A. 117, 5772-5781 (2020)
Verlagsversion DOI
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Posttranslational modifications (PTMs) are important physiological means to regulate the activities and structures of central regulatory proteins in health and disease. Small GTPases have been recognized as important molecules that are targeted by PTMs during infections of mammalian cells by bacterial pathogens. The enzymes DrrA/SidM and AnkX from Legionella pneumophila AMPylate and phosphocholinate Rab1b during infection, respectively. Cdc42 is AMPylated by IbpA from Histophilus somni at tyrosine 32 or by VopS from Vibrio parahaemolyticus at threonine 35. These modifications take place in the important regulatory switch I or switch II regions of the GTPases. Since Rab1b and Cdc42 are central regulators of intracellular vesicular trafficking and of the actin cytoskeleton, their modifications by bacterial pathogens have a profound impact on the course of infection. Here, we addressed the biochemical and structural consequences of GTPase AMPylation and phosphocholination. By combining biochemical experiments and NMR analysis, we demonstrate that AMPylation can overrule the activity state of Rab1b that is commonly dictated by binding to guanosine diphosphate or guanosine triphosphate. Thus, PTMs may exert conformational control over small GTPases and may add another previously unrecognized layer of activity control to this important regulatory protein family.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Posttranslational Modifications ; Nmr ; Protein Dynamics ; Small Gtpases; Effector Protein Drra; H-ras P21; Binding Domain; Legionella; Rab1; Substrate; Displacement; Mechanism; Complex; Enzymes
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Band: 117, Heft: 11, Seiten: 5772-5781 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Begutachtungsstatus Peer reviewed