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abstracts
Membrane traffic, which is the "cellular postal service" that shuttles biomolecules around the cell and organizes the structure of organelles, is among the primary targets of effectors injected by intracellular pathogenic bacteria to invade their host and avoid from being destroyed. I will present our recent structural and biochemical studies of effectors from Legionella pneumophila (the bacteria that causes the legionnaire's disease, a severe pneumonia) that divert membrane traffic to generate a membrane-bound vacuole where the pathogen hides and replicates. One of these effectors, AnkX, is a FIC domain-containing toxin that alters the functions of a Rab GTPase involved in vesicular traffic at the endoplasmic reticulum, by covalent attachment of a phosphocholine molecule. The other one, RalF, functions as an illegitimate guanine nucleotide exchange factor to activate an Arf GTPase on the vacuole. Our studies showed how AnkX binds and processes CDP-choline to transfer phosphocholine onto Rab1 [1], and uncover a novel membrane sensor in RalF that controls its localization and activity [2]
abstracts
The International Year of Crystallography coincides with the celebration of the 50th anniversary of the landmark articles on allostery by Monod, Changeux & Jabob (1963) and Monod, Wyman and Changeux (1965). These articles defined "allosteric" interactions in proteins as "indirect interactions between topographically distinct sites" and devised the model (now known as the MWC model) for the conformational changes mediating them. The concept, which Jacques Monod reportedly described as the "second secret of life" second only to the genetic code, was invented to account for feedback inhibition and cooperativity properties in enzymes and regulatory proteins, including hemoglobin. The pioneering crystallographic analysis of hemoglobin, whose structure had been determined by Max Perutz at about the same time, provided evidence for the concept and likely contributed to inspire it. Half a century later, allosteric interactions and underlying conformational transitions have been captured in many crystallographic structures, uncovering a wide range of mechanisms whereby information that affects biological activities is propagated over a long distance between two binding sites. I will present examples of allostery in protein crystallographic structures that illustrate the expansion and widespread application of the original concept, notably in understanding diseases and aiding in drug design.
