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Atomic insight into virulence factor translocation by Gram-negative bacterial type-II secretion systems

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  • Full or part time
    Dr Garnett
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Applications are invited for an EPSRC funded PhD studentship in Dr. James Garnett’s group at Queen Mary University of London.

Background: the research activity of the group is focused on understanding the key virulence traits of bacteria that allow them to establish infection and persist within the host and the environment. Many Gram-negative bacterial pathogens use a type-II secretion system (T2SS), a syringe-like mechanism, to transport protein substrates into their surroundings. These exported substrates have diverse roles including the formation/establishment of biofilms, subversion of host responses to infection and promoting intracellular host invasion/survival. Mutational analyses of several substrates belonging to different bacteria indicate that residues essential for secretion are distantly located and come together to form a conformational structure upon folding. However, with mutation-based approaches it is difficult to uncouple these events and as the T2SS targeting motif is a 3-dimensional one, a high-resolution structural strategy is essential. My group is currently focused on the molecular details of how substrates of the T2SS are recognized during secretion, as understanding this mechanism may provide new targets for the development of novel compounds in the fight against emerging antibacterial resistance. Our group takes a multidisciplinary approach in our research using a range of complementary structural biology procedures (X-ray crystallography, solution state NMR and SAXS) coupled with cellular, biochemical and other biophysical techniques. We also have strong links with the MRC Biomedical NMR Centre, the University of Birmingham HWB-NMR Centre, the Diamond Light Source synchrotron and Imperial College London. This provides an excellent training environment and the intellectual framework for a talented, postgraduate student to deliver a deeper understanding of the mechanisms that bacterial pathogens employ in the establishment of infections and persitence within the host/environment.

Aims:
(i) To determine the atomic structures of substrate/T2SS complexes
(ii) To study conformational changes within the T2SS upon substrate recognition
(iii) To confirm that these interactions are common in several bacterial T2SSs

Techniques and Training: the successful candidate will be trained in a wide range of biochemical and biophysical techniques to study T2SS proteins, including cloning, large-scale protein purification, X-ray crystallography, solution state NMR, SAXS, ITC, Biacore, DSF etc. Moreover, there will also be the opportunity to perform in vitro functional and also in vivo cell interaction assays, and the student will gain experience in Unix-based operating systems. The training will also include the development of skills essential for career progression, including management of research projects, presentation and writing skills. The aim is to equip the successful candidate with techiques and papers on which they can build a strong research career.

Environment: Queen Mary University of London is a member of the Russell group and is one of the leading research-focused institutions in the UK. All PhD students and post-doctoral researchers are part of the QMUL Doctoral College, which provides support with high-quality training and career development activities.

Application: for informal enquires please contact Dr. Garnett and include your CV, a covering letter explaining eligibility and interest in the project and the contact details of two academic referees.

Funding Notes

This EPSRC studentship will cover tutition fees and provide an annual tax-free maintenance allowance for 3.5 years at Research Councils UK rates. For eligibility for EPSRC studentship funding please see: https://www.epsrc.ac.uk/skills/students/help/eligibility. Candidates must have, or expect to have, a first or upper-second class degree in Biochemistry, Chemistry, or related subject appropriate for this project. An MSc in appropriate subject and laboratory experience may be an advantage, but are not essential.

References

Korotkov, KV, Sandkvist, M. & Hol, WG: The type II secretion system: biogenesis, molecular architecture and mechanism. Nature Rev. Microbiol. 10 (2012) 336-51.

Cianciotto, NP: Many substrates and functions of type II secretion: lessons learned from Legionella pneumophila. Future Microbiol. 4 (2009) 797–805.

Garnett, JA & Matthews, S: Interactions in bacterial biofilm development: a structural perspective. Curr. Prot. Pept. Sci. 13 (2012) 739-755.

Pakharukova, N, Garnett, JA, Tuittila, M, Paavilainen, S, et al: Structural insight into archaic and alternative chaperone-usher pathways reveals a novel mechanism of pilus biogenesis. PLoS Path. 11, (2015) e1005269.

Garnett, JA, Martínez-Santos, VI, Saldaña, Z, Pape, T, et al: Structural insights into the biogenesis and biofilm formation by the E. coli common pilus. PNAS 109 (2012) 3950-3955.

Miliara, X, Garnett, JA, Tatsuta, T, Abid, A, et al: Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes. EMBO Rep. 16 (2015) 824-35.

Garnett, JA, Muhl, M, Douse, C, Busch, B, et al: Pseudomonas aeruginosa Tps4 two-partner secretion system is involved in CupB5 translocation. Prot. Sci. 24 (2015) 670-687.

How good is research at Queen Mary University of London in Chemistry?

FTE Category A staff submitted: 14.00

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