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Mechanisms of molecular recognition by the prokaryotic argonautes


   School of Biochemistry


Bristol United Kingdom Biochemistry Biophysics Molecular Biology Structural Biology

About the Project

The discovery of CRISPR-Cas has been one of the most important scientific breakthroughs of the 21st century. The programmable sequence-specific interactions between Cas enzymes, such as Cas9, and DNA have been harnessed to produce revolutionary tools for gene editing and diagnostics. A recent real-world application has been the use of CRISPR-Cas for the detection of SARS-Cov2 genomic RNA in clinical samples. This "CRISPR revolution" has been contingent on many biochemical and biophysical studies that shed light on the molecular mechanisms of Cas9 and related enzymes. Crucially, Cas9 is only one of many prokaryotic enzymes that interact with DNA in a sequence-specific manner that can be adapted for research or clinical applications. To exploit these alternative DNA-interacting proteins requires deep insight into the way that they recognise their DNA targets. In this collaborative project between the Szczelkun lab (Bristol) and the Westra lab (Exeter), you will study molecular recognition by a newly identified bacterial defence system, the prokaryotic argonautes (pAgos), in order to lay the foundations for the development of novel tools in the future.

Compared to their eukaryotic homologues, the roles and mechanisms of the pAgos are poorly defined. You will use microscopy (single-molecule magnetic and optical tweezers) and other techniques to explore these mechanisms. Recent data suggests interactions with host proteins trigger a DNA-guided DNA cleavage activity of pAgo. You will establish single-molecule microscopy assays using purified components to directly observe the steps in molecular recognition. These assays can be adapted to include the host proteins that play a role in pAgo biology. In addition to single-molecule techniques, you will gain experience in protein expression and engineering, and in biochemical enzyme assay design and implementation. You will be based in the Szczelkun lab which is supported by funding from the BBSRC and ERC, and is part of the thriving and collegiate School of Biochemistry at the University of Bristol. There will be close collaboration with the Westra lab in Exeter. For more information on the team, see www.bristol.ac.uk/biochemistry/people/markd-szczelkun/overview.html.


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