Evolving and Engineering Biomolecules
Leader: Professor Renwick Dobson
Under this flagship theme, we are exploring fundamental questions of how molecules evolve, function and interact. We are focused on harnessing biomolecular interactions, creating enzymes with novel properties, rewiring cells to produce biomolecules in short supply, utilising long-term evolution experiments to better understand structure, function and evolution and mining evolutionary diversity for new function.
BIC Director Professor Renwick Dobson has received a prestigious 2019 Marsden Fund grant to unravel the mechanism by which a family of proteins called Tripartite ATP-independent periplasmic (TRAP) transporters move essential nutrients across cell membranes.
Joining Professor Dobson in this study are Associate Professor Jane Allison (University of Auckland), Dr Rachel North (UC) and Professor Soichi Wakatsuki (School of Medicine, Stanford University). Collectively, their expertise spans biophysics, structural biology and molecular modelling.
As well as providing fundamental insights on molecular activities, their findings could produce other far-reaching benefits. “This knowledge will drive a better understanding of bacterial pathogenicity and colonisation, and underpin the future development of new antibiotics to combat harmful bacteria,” says Professor Dobson.
There is an urgent need for cheap and effective screening devices that can be used in non-clinical settings. Diabetes is a good example, due to its rapidly expanding incidence in the population.
Professor Renwick Dobson’s team recently demonstrated that peptide fibrils reversibly form hydrogels, creating stimuli-responsive hydrogel membranes. Using this technology, Professor Dobson’s team will be working to produce a proof-of-concept assay device that will monitor the passage of blood though the stimuli-responsive hydrogel membrane, which is dependent on the concentration of glycated haemoglobin, an accepted and universal biomarker for diabetes. To inform the engineering and design of the assay platform, Professor Dobson’s group will first need to understand how the peptide self-assembles into hydrogels and how they can control reversible assembly and disassembly.
This novel assay will have broad application due to its simplicity, ease of use, and temperature tolerance. This will allow screening tests to be undertaken in remote and adverse environments by relatively untrained users. Future development of the platform will seek to develop simple assay test solutions to address water-testing issues in remote areas and “pen-side” testing for animal diseases.
The protein Smchd1 (structural maintenance of chromosomes flexible hinge domain containing 1) is an epigenetic repressor. It has been shown to play an essential role in autosomal and X-linked gene repression, with critical consequences for normal biology and disease, particularly facioscapulohumeral muscular dystrophy. The underlying molecular mechanism by which Smchd1 functions is unknown. The work provides the first biochemical and biophysical evidence that Smchd1–chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. The results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonise other chromatin interactions, resulting in coordinated transcriptional control.
The work on the understanding of complex allosteric mechanisms for the control of enzyme activity has continued in the lab of Emily Parker. A new collaboration with Eileen Jaffe (Fox Chase Cancer Center, Philadelphia) assisted with the understanding of the way in which the human enzyme phenylalanine hydroxylase operates. Mutations to this enzyme are the cause of the phenylketonuria, the most common inborn error of amino acid metabolism. Research has also continued with understanding the complexity of regulation for the shikimate pathway. Complex domain movements were shown for the Geobacillus sp. 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAH7PS), and this work was highlighted in the 'Journal of Biological Chemistry'. PhD students Eric Lang and Logan Heyes' study of the dynamic networks involved in the allostery was published in the 'Journal of the American Chemical Society'.