Helen O'Hare

Molecular mechanisms of sensory perception and metabolic regulation in bacteria

Research Summary

The main aim of my research group is to determine the molecular mechanisms by which bacteria sense and respond to their environment, with a particular focus on protein kinase G in the human pathogen Mycobacterium tuberculosis.

Phosphorylation at serine and threonine emerged as a ubiquitous mechanism of signal transduction in bacteria from genome sequencing in the 1990s. Serine and threonine protein kinases are now known to regulate critical bacterial processes including central carbon metabolism and cell division, but identification of the stimuli of kinase activation and the downstream effects of kinase activation are outstanding questions in the field.

My group study the complete PknG signalling pathway, from activation by amino acids to the downstream roles of kinase substrates in regulating central metabolism, with the result that PknG is one of only a handful of bacterial S/T kinases for which the activation stimuli are known, and arguably the only bacterial FHA-mediated signalling pathway with a complete molecular description (FHA=forkhead associated domain, a ubiquitous phospho-threonine recognition domain).

We are also working on the conserved pathways in the industrial “workhorse” Corynebacterium glutamicum (used to produce >$6 billion dollars of amino acids per year) and the antibiotic producing Streptomyces (>$1billion dollar market).

We collaborate with groups within the institute and Departments of Infection, Immunity and Inflammation and Molecular and Cell Biology to validate anti-TB drug targets and for structure based drug discovery (Russell Wallis), to study protein phosphorylation at the level of the phosphoproteome and in regulation of bacterial cell growth (Galina Mukamolova), and to study the function of these signalling pathways in infection models (Leicester TB Research Group).

Crystal structure of GlnH with aspartate

Crystal structure of GlnH with aspartate

 

 

 

 

 

 

 

 

Crystals of M. tuberculosis GlnH
Crystals of M. tuberculosis GlnH (1)Crystals of M. tuberculosis GlnH (2)

Alignment of crystal structures of GlnH in complex with different amino acid ligands

Alignment of crystal structures of GlnH in complex with different amino acid ligands

Transmission electron micrograph showing the cell morphology and cell envelope structure of Mycobacterium smegmatis
Negative stain transmission electron micrograph showing the cell morphology and cell envelope structure of Mycobacterium smegmatis

Key Publications

Bhattacharyya N, Nkumama IN, Newland-Smith Z, Lin LY, Yin W, Cullen RE, Griffiths JS, Jarvis AR, Price MJ, Chong PY, Wallis R, O’Hare HM (2018) An aspartate-specific solute-binding protein regulates protein kinase G activity to control glutamate metabolism in Mycobacteria. mBio 9(4): mBio00931-18.

Rieck B, Degiacomi G, Zimmermann M, Cascioferro A, Boldrin F, Lazar-Adler NR, Bottrill AR, le Chevalier F, Frigui W, Bellinzoni M, Lisa MN, Alzari PM, Nguyen L, Brosch R, Sauer U, Manganelli R, O’Hare HM (2017) PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis. PLoS Pathog 13(5): e1006399.

Ventura M, Rieck B, Boldrin F, Degiacomi G, Bellinzoni M, Barilone N, Alzaidi F, Alzari PM, Manganelli R, O'Hare HM (2013) GarA is an essential regulator of metabolism in Mycobacterium tuberculosis. Mol Microbiol. 90(2):356-66.

Nott TJ, Kelly G, Stach L, Li J, Westcott S, Patel D, Hunt DM, Howell S, Buxton RS, O’Hare HM, Smerdon SJ (2009) An intra-molecular switch regulates phospho-independent FHA domain interactions in Mycobacterium tuberculosis. Science Signaling 2 (63) ra12.

Group members

Sarah Pallett, Zac Newland-Smith, Iswahyudi Alamsyah, Kawther Alqaseer (with Galina Mukamolova) and Enass Al-Mkhadree (with Mike Barer)

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