Dr Rosemary Cater

A new approach to investigating the blood-brain barrier

The blood-brain barrier (BBB) is a highly selective semipermeable barrier that separates the blood from the brain. It plays a critical role in maintaining homeostasis in the brain and the activation of the central nervous system. Transporters expressed at the BBB serve as the gatekeepers of this boundary, selectively allowing the passage of essential nutrients into the brain while preventing the entry of potentially harmful substances. While this barrier evolved to protect our brains from harm, it also prevents ~98% of all small-molecule drugs from entering the brain. This creates a major bottleneck in the development of treatments for brain diseases such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, anxiety, and depression.

The overarching goal of the Cater Lab is to understand the molecular mechanisms of transport at the blood-brain barrier. We employ a multidisciplinary approach, encompassing cryo-electron microscopy (cryo-EM), biochemistry, and biophysics to unravel the molecular details underpinning how transporters at the BBB allow specific molecules to cross this barrier. By dissecting these mechanisms, we hope to not only understand more about how the brain acquires nutrients critical for its function but also to provide insights into designing neurotherapeutics so that they can be smuggled into the brain via these transporters.

Group leader

Dr Rosemary Cater

Group Leader, Molecular mechanisms of blood-brain barrier transport

+61 7 3346 2016
r.cater@uq.edu.au
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- Rosemary J. Cater**^†, Dibyanti Mukherjee^†, Eva Gil-Iturbe, Satchal K. Erramilli, Ting Chen, Katie Koo, Nicolás Santander, Andrew Reckers, Brian Kloss, Tomasz Gawda, Brendon C. Choy, Zhening Zheng, Aditya Katewa, Amara Larpthaveesarp, Eric J. Huang, Scott W. J. Mooney, Oliver B. Clarke, Sook Wah Yee, Kathleen M. Giacomini, Anthony A. Kossiakoff, Matthias Quick, Thomas Arnold**, Filippo Mancia** (2024). Structural and molecular basis of choline uptake into the brain by FLVCR2. BioRxiv: doi:10.1101/2023.10.05.561059.
- Shana Bergman^†, Rosemary J. Cater^†, Ambrose Plante, Filippo Mancia & George Khelashvili (2023). Substrate binding-induced conformational transitions in the ω-3 fatty acid transporter MFSD2A. Nature Communications. 14(1):3391. PubMed PMID: 37296098.
- Rosemary J. Cater, Geok Lin Chua, Satchal K. Erramilli, James E. Keener, Brendon C. Choy, Piotr Tokarz, Cheen Fei Chin, Debra Q.Y. Quek, Brian Kloss, Joseph G. Pepe, Giacomo Parisi, Bernice H. Wong, Michael T. Marty, Oliver B. Clarke, Anthony A. Kossiakoff, George Khelashvili**, David L. Silver**, & Filippo Mancia** (2021). Structural basis of ω-3 fatty acid transport across the blood-brain barrier. Nature. 595(7866):315-319. PMID: 34135507.
- Jonathan Kim*, Rosemary J. Cater*, Brendon C. Choy, & Filippo Mancia (2021). Structural insights into transporter-mediated drug resistance in infectious diseases. Journal of Molecular Biology. 433(16):167005. PMID: 33891902.
- Ichia Chen^†, Shashank Pant^†, Qianyi Wu^†, Rosemary J. Cater, Meghna Sobti, Robert J. Vandenberg, Alastair G. Stewart, Emad Tajkhorshid**, Josep Font**, & Renae M. Ryan** (2021). Glutamate transporters have a chloride channel with two hydrophobic gates. Nature. 591(7849):327-331. PMID: 33597752.
- Brendon Choy^†, Rosemary J. Cater^†, Filippo Mancia**, & Edward E. Pryor, Jr.** (2021). A 10-year meta-analysis of membrane protein structural biology: Detergents, membrane mimetics, and structure determination techniques. BBA-Biomembranes. 1863(3):183533. PMID: 33340490.
- James R. Krycer^†, Daniel J. Fazakerley^†, Rosemary J. Cater, Kristen C. Thomas, Sheyda Naghiloo, James G. Burchfield, Sean J. Humphrey, Robert J. Vandenberg, Renae M. Ryan, & David E. James (2017). The amino acid transporter, SLC1A3, is plasma membrane-localized in adipocytes and its activity is insensitive to insulin. FEBS letters. 591(2):322-330. PMID: 28032905.
- Rosemary J. Cater, Robert J. Vandenberg, & Renae M. Ryan (2016). Tuning the ion selectivity of glutamate transporter associated uncoupled conductances. Journal of General Physiology. 148 (1):13-24. Selected to feature on the cover of the July 2016 issue. PMID: 27296367.
- Rosemary J. Cater, Renae M. Ryan, & Robert J. Vandenberg (2016). The Split Personality of Glutamate Transporters: A Chloride Channel and a Transporter. Neurochemical Research. 41(3):593-9. PMID: 26303507.
- Rosemary J. Cater, Robert J. Vandenberg, & Renae M. Ryan (2014). The Domain Interface of the Human Glutamate Transporter EAAT1 Mediates Chloride Permeation. Biophysical Journal 107(3):621-9. PMID: 25099801. Featured as a New and Notable article.

^† Denotes equal contribution

** Denotes equal co-correspondence

The following are a list of current PhD opportunities at the Cater Lab. If you are interested in any of the below please reach out to Dr Cater via email (r.cater@uq.edu.au) with your CV attached.

1. Understanding the molecular structures of proteins involved in rare disease.

Rare diseases are often caused by genetic mutations that disrupt protein function. In some cases, we already understand the three-dimensional structure and functional role of these proteins in healthy individuals. However, unfortunately, for some rare diseases, we lack this knowledge. This lack of information prevents us from understanding how mutations within the protein can lead to malfunction and disease onset, which in turn prevents us from understanding the disease and how to treat it. This project will employ biochemical techniques, structural biology (cryo-EM), and computational approaches to understand the normal 3D structure and role of proteins implicated in rare diseases. By elucidating these aspects, we will provide critical insights for the development of drugs to treat these rare diseases.

2. Characterization of blood-brain barrier nutrient transporters

The blood-brain barrier (BBB) is a layer of tightly packed endothelial cells that separate the blood for the brain. The BBB has evolved to protect our brains from blood-borne neurotoxins and pathogens, but unfortunately, it also prevents the majority of potential neurotherapeutics from entering the brain. In fact, it has been estimated that ~98% of all small-molecule drugs are not able to cross the BBB. This creates a major bottleneck in the development of treatments for diseases such as Parkinson’s disease, Alzheimer’s disease, glioblastoma, anxiety, and depression. The more we know about what can enter the brain, the better informed we will be for developing treatments for these diseases. Transporter proteins expressed at the BBB play a very important role in regulating the entrance of molecules in a highly specific manner. For example, the transporters FLVCR2 and MFSD2A allow for the uptake of choline and omega-3 fatty acids into the brain – both of which are essential nutrients that the brain requires in very large amounts. This project will utilise biochemical techniques and structural biology (cryo-EM) to further understand transport proteins at the BBB and how they transport specific molecules into the brain. This will provide critical insights that for the development of neurotherapeutics that can hijack these transporters to allow for entrance into the brain.

3. (Earmark) Understanding how blood vessels in the brain are formed

The human brain comprises ~650 kilometres of blood vessels lined by brain endothelial cells, which supply the brain with oxygen and essential nutrients. The growth of cerebral blood vessels begins early in development via a process called sprouting angiogenesis. Despite its importance, the molecular mechanisms underlying brain angiogenesis and formation of the blood-brain barrier are poorly understood. It has recently been demonstrated that the gene Flvcr2 is critical for blood vessels to grow in the brain, and last year we discovered that the protein encoded by this gene (FLVCR2) transports choline – an essential nutrient – across the blood brain barrier and into the brain. This project will utilise biochemical techniques and structural biology (cryo-EM) to investigate what other molecules may regulate this transport process, and how choline regulates angiogenesis in the brain.

The Cater Lab is always looking for talented post-doctoral researchers to study the structure and function of membrane proteins using single-particle cryo-EM and other techniques.

Postdoctoral Fellows will be responsible for the expression, purification and structure determination of proteins involved in membrane transport, human physiology, and disease pathology. They will also be responsible for biophysical and biochemical characterization of target proteins, which may include characterization of protein-ligand or protein-protein interactions. Candidates must have a Ph.D. in Structural Biology, Molecular Biology, Biochemistry, or related fields. Preference will be given to candidates who have experience in membrane protein expression/purification and/or single-particle cryo-EM, and who bring their own funding. Good communication and organizational skills and the ability to work independently are also critical for this position. Salary will be commensurate with the candidate's experience and will be based on the University of Queensland’s Enterprise Agreement.

The UQ Centre for Microscopy and Microanalysis is located just down the hall from the Cater lab and provides access to cryo-EM and cryo-ET instrumentation including: a Thermo Scientific 200 keV Glacios (currently being set up), a 200 keV Jeol Cryo-ARM200, a 300 keV Jeol Cryo-ARM300, a Leica UC6-FCS Cryo-Ultramicrotome, an FEI Vitrobot, a Leica EM GP2 plunge freezer, and more!

The Cater Lab is located at the University of Queensland’s St Lucia Campus in Brisbane – just 15 minutes from the heart of the city! Brisbane (population 2.3 mil) is a vibrant and multicultural city that boasts a subtropical climate and will host the Summer Olympic Games in 2032.

Candidates will be evaluated on a rolling basis. For further information, candidates can contact Dr Cater via email (r.cater@uq.edu.au) or direct message on X/Twitter (@RosemaryJCater) or LinkedIn.