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STRUCT4LEG Report Summary

Project ID: 321630
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - STRUCT4LEG (Structural biology of Legionella’s effectors and secretion system)

The funded research programme addressed issues of secretion by the bacterial pathogen, Legionella pneumophila. In this bacterium, secretion is mediated by a type IVB secretion system (T4BSS). T4BSS is composed of circa 20 components forming a secretion apparatus. It secretes more than 300 effectors into host cells. Mechanistically, this system is poorly understood. Prior to secretion, effectors are thought to be bound to a(several) chaperone(s), including IcmSW, which maintain them in a semi-unfolded state. Those effector-chaperone complexes are recruited to the secretion apparatus by a so-called “coupling complex” made of 3 proteins, DotLMN. We have worked on elucidating the structures of i) the secretion apparatus, ii) the coupling complex, and iii) the effectors. Major achievements have been in the second and third areas of investigation where several crystal structures of effectors and also DotM have been obtained. Legionella secrete a very large number of effector proteins. How these effectors are targeted to the transport T4BSS machinery is unknown. By solving the structure of DotM, we have found that this protein serves as a platform for recruitment of effectors that have a particularly acidic signal sequence at their N-terminus. Our efforts on ascribing function to effector proteins have been met with similar success: we have solved the structure of two phosphatases, WipA and WipB, and have shown that, although they have very similar structures, their functions are very different, one acting as a phosphotyrosine phosphatase (WipA) while the other functions as a phosphoserine phosphatase. Extensive biochemical studies have revealed that WipA can dephosphorylate selectively the FGF receptor and WipB functions in acidified LAMP1-positive lysosomal compartments, where WipB interacts with the v-ATPase and the associated LAMTOR1 phosphoprotein, key components of the lysosomal nutrient sensing (LYNUS) apparatus that controls the mammalian target of rapamycin (mTORC1) kinase complex at the lysosomal surface.

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United Kingdom
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