The Newstead group is a vibrant, dynamic team of researchers with a shared goal to understand and explain the molecular basis for SLC transporter function in health and disease.
Transporters belonging to the Solute Carrier (SLC) family are integral membrane proteins that play essential roles in human physiology. They predominantly function to regulate the transport of small molecules into and out of cells and regulate the availability of amino acids, ions, sugars, lipids and vitamins within the body. SLC transporters also function within intracellular signalling networks, particularly with respect to amino acid and nutrient sensing.
Specifically, research in my group focuses on understanding how nutrient transporters function at a molecular level. In humans, many of the membrane proteins involved in absorbing nutrients from our diet are also responsible for drug transport and distribution into specific organs, including the central nervous system, liver, kidneys and GI tract. Nutrient transporters therefore have a profound impact on the pharmacokinetic properties of many administered drugs with clear medical advantages in understanding their structure, biochemistry and regulation.
The lysosome is a major metabolic signalling hub in the cell, largely through the actions of the mTOR kinase complex, which regulates metabolic pathways in response to cytoplasmic nutrient availability and C9ORF72, which regulates membrane trafficking. Dysregulation of lysosomal function leads to several neurodegenerative diseases, including Parkinsons disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral screlosis (ALS).
Amino acid transporters have emerged as important regulators of mTOR signalling and C9ORF72 activity, either directly through protein interactions or functioning as scaffolds, around which complex signalling systems are assembled in the lysosomal membrane. How mutations in these proteins result in disease however is still far from certain, hampering efforts to develop treatments and fundamentally, to understand the role of lysosomal function in human health and disease.
Recently we discovered that the KDEL receptor is structurally related to a family of SLC transporters involved in lysosomal homeostasis, catalysing our discovery research in this area. Building on this foundtation, we are now exploring the mechanistic and functional links between transporters, trafficking receptors and signalling function in the cell. A key goal is to understand the molecular basis for SLC mediated signalling and open new avenues for therapeutic intervention.
The group is currently working on several families of proton coupled SLC transporters. These include the SLC15 peptide transporters, PepT1 and PepT2, the amino acid transporters SLC7, 36 and 38 and the SLC46 family of proton coupled folate transporters. Additionally we have an MRC funded project looking at understanding fungal nucleotide sugar transporters as novel targets for new generation antifungals and as model systems for understanding organisation within the Golgi apparatus. To achieve these aims we are developing novel antibody binders to regulate transport and trafficking in the cell.
We are a structural and biochemistry focused group, using a range of biophysical and biochemical methods. Our main techniques are protein crystallisation and single particle cryo-EM imaging. We also rely heavily on insights gained through detailed biochemical analysis of reconstituted protein and functional assays. Our research has resulted in several commercial products in the area of membrane protein structural biology. Please see the individual pages for specific projects, research papers, review articles and book chapters; I hope you enjoy the site.