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Katherine Fenn

Katherine

PhD student

Email: k.fenn@qmul.ac.uk

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Project title: Characterisation of Mammalian Cell Entry (Mce) proteins from the mce4 operon of Mycobacterium tuberculosis

Summary: Mycobacterium tuberculosis (MTB) causes the infectious disease Tuberculosis (TB). According to the World Health Organisation which ranks TB as a top 10 cause of death, there were 10.4 million new cases of TB in 2015. It is estimated one third of the world’s population is latently infected with MTB and 10% of these infections result in TB. The prevalence of latent infections is due to the evasion of immune responses leading to prolonged dormancy of MTB in host cells.
An important strategy for ending the TB epidemic is understanding the mechanisms of MTB invasion and survival in macrophages. Mammalian cell entry (Mce) proteins have been proposed to have important functions in host cell invasion, survival and nutrient utilisation. The Mce proteins of MTB are located on four homologous operons (mce1-4) in clusters of six (A-F). The redundancy of the operons relates to their varying and time-dependent functions. The mce4 operon has been implicated in long-term survival of the mycobacterium whilst the mce1 operon in early phases of infection. Mutations in each operon attenuate MTB virulence and deletion of mce4 operon has the highest effect on MTB virulence. Each operon consists of two additional genes for two integral membrane proteins. The eight proteins of each operon assemble into Mce transport systems (MTS) resembling ABC-like transporter systems. The components of mce4 operon have been proposed to represent a cholesterol import system of MTB aiding mycobacterium survival by its use of cholesterol as a nutrient source.
The E. coli Mce proteins have recently been demonstrated to encode proteins involved in the transport of lipids and hydrophobic molecules important for outer membrane lipid asymmetry. Mce proteins contain a conserved Mce domain which is ubiquitous among double-membraned bacteria and eukaryotic chloroplasts. In E. coli the structures of three Mce proteins have been elucidated; MlaD forms a homo-hexamer ring of the Mce domain associated with an ABC-transporter on the inner membrane whilst YebT and PqiB form elongated structures of stacked Mce domain hexameric rings spanning the periplasmic space. It is unknown whether the 6 Mce proteins from an MTB operon form a hetero-hexamer similar to the E. coli MlaD hexamer ring or the proteins form stacks of hexamer rings such that the complex will span the mycobacterial cell wall. The E. coli Mce protein structures were the first structural evidence of this domain and there is no detailed structural information for any of the MTB Mce proteins.
This project will focus on understanding the structure-function relationship of the Mce4 proteins. The Mce domain from each Mce4 protein will be examined to understand their role in forming a cholesterol/lipid transport channel.

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