Reference

PNAS. 114 (52), 11151-11160. DOI:10.1073/pnas.1715361115 portada0118

Authors

Miguel Romano-Moreno, Adriana L. Rojas, Chad D. Williamson, David C. Gershlick, María Lucas, Michail N. Isupov, Juan S. Bonifacino, Matthias P. Machner, and Aitor Hierro.

Abstract

Microbial pathogens employ sophisticated virulence strategies to cause infections in humans. The intracellular pathogen Legionella pneumophila encodes RidL to hijack the host scaffold protein VPS29, a component of retromer and retriever complexes critical for endosomal cargo recycling. Here, we determined the crystal structure of L. pneumophila RidL in complex with the human VPS29–VPS35 retromer subcomplex. A hairpin loop protruding from RidL inserts into a conserved pocket on VPS29 that is also used by cellular ligands, such as Tre-2/Bub2/Cdc16 domain family member 5 (TBC1D5) and VPS9-ankyrin repeat protein for VPS29 binding. Consistent with the idea of molecular mimicry in protein interactions, RidL outcompeted TBC1D5 for binding to VPS29. Furthermore, the interaction of RidL with retromer did not interfere with retromer dimerization but was essential for association of RidL with retromer-coated vacuolar and tubular endosomes. Our work thus provides structural and mechanistic evidence into how RidL is targeted to endosomal membranes.

 

Description

La legionelosis o enfermedad del legionario es una neumonía potencialmente fatal, causada por la bacteria Legionella pneumophila. Durante la infección, la bacteria trasloca un gran número de proteínas, llamadas efectores, al interior de la célula hospedadora para facilitar su supervivencia y replicación intracelular. En este trabajo hemos determinado como RidL, un efector de L. pneumophila, manipula un complejo de transporte intracelular llamado retrómero y compitiendo con diferentes factores intracelulares. Este trabajo no solo ayuda a comprender mejor la actividad del retrómero durante el tráfico intracelular, sino que además permite la identificación de nuevas dianas con potencial terapéutico.

 

 

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de “Intracellular membrane trafficking” del CIC bioGUNE, dirigido por Aitor Hierro, investiga mecanismos de transporte en Endosomas, un orgánulo central en la redistribución de proteíans celulares. El grupo utiliza una aproximación multidisciplinar que incluye técnicas estructurales, bioquímicas y de biología celular para elucidar las redes proteicas que codifican la selección de receptores, y la organización estructural de estos complejos multiproteicos en vesículas de transporte.

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