Professor Renae Ryan
School of Biomedical Engineering
School of Medical Sciences
Australian Research Council Future Fellow
Renae Ryan (she/her) received her PhD from the University of Sydney in 2004. After working as a postdoctoral fellow at Columbia University and the National Institutes of Health in the USA, Renae returned to the University of Sydney and was appointed as Associate Professor in the Sydney Medical School in 2010. Professor Ryan leads a research team that uses structural biology and biophysical techniques to investigate the molecular mechanisms of neurotransmitter and amino acid transporters and their role in cancer and neurological diseases, such as episodic ataxia.
Cells from all life forms are surrounded by a lipid membrane containing transport proteins that control the movements of molecules into and out of cells and are vital for a plethora of physiological processes including cell-to-cell communication, obtaining nutrients, and extruding waste. Professor Ryan is an internationally recognised expert in elucidating the fundamental molecular mechanisms of transport proteins. She has dedicated her career to understanding the structure and mechanism of amino acid transporters from the glutamate transporter family, which are found across all domains of life. In humans, they perform the essential role of regulating the excitatory neurotransmitter glutamate to ensure normal brain function and are important in amino acid homeostasis throughout the body. Dysfunction of these transporters is linked to several neurological diseases and in cancer, they are upregulated to increase amino acid uptake to fuel rapid and uncontrolled cell growth.
Glutamate transporters are enigmatic dual function proteins that also possess chloride channel activity, two processes thought to be structurally and mechanistically distinct. A seminal discovery by Professor Ryan early in her career uncovered that these dual functions were mediated by distinct conformational states of the protein. She solved some of the earliest X-ray crystal structures of transporters in this family revealing an unusual trimeric architecture where three subunits come together to form a “triple twisting elevator”, each subunit able to support the dual functions independently.
Professor Ryan and her research teamcombine functional analysis of membrane transporters with structural biology techniques to uncover the molecular choreography of these interesting transporters and have revealeda direct link between the unique twisting elevator mechanism and the dual trnasporter/channel functions. They are also dedicated to understanding disease-causing mutations in these proteins linked to amino acid disorders and neurological diseases such as episodic ataxia (EA6), a disease characterised by periods of severe incoordination and paralysis and associated with migraine. Professor Ryan leads a multi-disciplinary team that investigates episodic ataxiapatient-derived mutations in human glutamate transporters revealing both increases and decreases in the chloride channel function, rather than changes in the glutamate transporter function, are disease-causing. These exciting new findings reveal a direct link between the chloride channel and disease and raise interesting questions about the physiological role of the chloride channel function.
Professor Ryan teaches into third year Pharmacology and Physiology courses (PCOL3012, PCOL3022 and PHSI3009), the Medical Program and the Doctor of Dental Medicine.
Former postgraduate students:
- Chelsea Briot (2024)
- Natasha Freidman (2021)
- Ichia Chen (2021)
- Qianyi Wu (2020)
- Shannon Mostyn (2018)
- Rosemary Cater (2017)
- Benjamin McIlwain (2016)
- Amanda Scopelliti (2015)
- Reem Bashour (2013)
- Amelia Edington (2012)
- Tan Sirivanta (2011)
Honours/Masters/PhD projects are availble in the lab. Please reach out to disucss further.
1. Molecular Mechanisms of Glutamate Transporters
We use structural biology and biophysical techniques to investigate the molecular mechanisms of neurotransmitter and amino acid transporters. The aim of this project is to develop a structural model for transporters from the dual function glutamate transporter family (SLC1A). This family includes the human glutamate transporters (EAATs) and neutral amino acid transporters (ASCTs) that can also function as chloride channels. We aim to understand how these transporters malfunction in neurological disease states (eg. episodic ataxia) and in cancer. This information is then used to develop therapeutics that are both transporter-specific and subtype selective to treat these disorders.
2. How do biologically inert probes enter cancer cells?
All cells have transporter proteins for the controlled uptake of nutrients such as amino acids, sugars, and folates. These transporter proteins are expressed at unusually high levels in cells where the demand for particular nutrients is greater, such as in cancer cells. The differential expression of nutrient transporter proteins is a useful marker of cell type and can be harnessed to promote the selective accumulation of biologically inert probes to deliver bioactive agents into cancer cells. The aim of this project is to develop a series of amino acid- and folate-based probes and then determine which membrane transporters allow them to enter cancer cells.
This ARC funded project is a collaboration E/Prof Trevor Hambley in the School of Chemistry.
- Asian Biophysics Association - Secretary General
- Australian Physiology Society
- Australian Society for Biophysics
- Biophyscial Society - Australian Ambassador
- Lorne Conference on Protein Structure and Function - Secretary
- International Society for Neurochemistry
- International Transmembrane Transporter Society - Vice-President
- Member of the Order of Australia (2023)
- Nancy Millis Medal, Australian Academy of Science (2023)
- Australian Museum Eureka Prize for Outstanding Mentor of Young Researchers (2023)
- Sharona Gordon Award for Transformational Leadership (2023)
- Fellow of the Royal Society of NSW (2023)
- Edna Award, for women that have made a feminist difference - Workforce category (2022)
- Sydney University Postgraduate Representative Association ‘Supervisor of the Year Award’ (2021)
- Vice-Chancellor's Award for Outstanding Mentoring and Leadership (2019)
- Women's Agenda Leadership Awards Finalist (2018)
- JA Young Medal, Sydney Medical School (2017)
- Outstanding Mentoring and Leadership, Sydney Medical School Excellence Award (2017)
- NSW Tall Poppy Award, Australian Institute of Policy and Science (2012)
- AK McIntyre Prize, Australian Physiological Society (2010)
- Young Investigator Award, Lorne Protein Conference (2008)
- Dennis Wade Johnson & Johnson New Investigator Award, Australasian Society of Clinical and Experimental Pharmacology and Toxicology (2007)
- Barbara EllLecturer, Victor Chang Cardiac Research Institute (2007)
- Rebecca Cooper Medal, Bosch Institute (2007)
- Best Postdoctoral Publication Prize, Australian Physiological Society (2007)
(McGill University Centre for Research in Neuroscience) Prof Don van Meyel; the role of the chloride conductance of the human glutamate transporters in Episodic Ataxia. | |
(Department of Physiology and Biophysics, Weill Cornell Medical College) Professor Olga Boudker; structural studies of membrane transport proteins. | |
(NYU Grossman School of Medicine) Dr Nicolas J. Abreu, MD; human glutamate transporter mutations linked to episodic ataxia type-6 | |
(University of Illinois at Urbana-Champaign) Professor Emad Tajkhorshid; Molecular dynamics simulations of membrane transporters |
| Project title | Research student |
|---|---|
| How do biologically inert probes enter cancer cells? | Bronte CARROLL |
| Pharmacological and biochemical modulation of the chloride conductance in glutamate transporters | Amy CHENG |
| The Lipid Allosteric Site: A Novel Drug Target for Solute Carrier 6 Transporters | Irina LOTSARIS |
| Elucidating the link between glutamate transporters and the pathogenesis of episodic ataxia | Emily ZHOU |
Publications
Book Chapters
- Carland, J., Edington, A., Scopelliti, A., Ryan, R., Vandenberg, R. (2013). Directed Mutagenesis in Structure Activity Studies of Neurotransmitter Transporters. In David Figurski (Eds.), Genetic Manipulation of DNA and Protein - Examples from Current Research, (pp. 167-184). Rijeka: InTech Publishers. [More Information]
- Ryan, R., Boudker, O. (2013). Glutamate Transporter Family. In Gordon C. K. Roberts (Eds.), Encyclopedia of Biophysics, (pp. 893-900). Heidelberg: Springer.
- McKinzie, A., Ryan, R., Vandenberg, R. (2010). Site-Directed Mutagenesis in the Study of Membrane Transporters. In Qing Yan (Eds.), Membrane Transporters in Drug Discovery and Development: Methods and Protocols - Methods in Molecular Biology Volume 637, (pp. 277-293). New York: Humana Press. [More Information]
Journals
- Nolan, K., Rosser, C., Wood, J., Font Sadurni, J., Sresutharsan, A., Wang, J., Markham, T., Ryan, R., Codd, R. (2024). An elastic siderophore synthetase and rubbery substrates assemble multimeric linear and macrocyclic hydroxamic acid metal chelators. Chemical Science. [More Information]
- Zeng, Y., Sobti, M., Quinn, A., Smith, N., Brown, S., Vandenberg, J., Ryan, R., O'Mara, M., Stewart, A. (2023). Structural basis of promiscuous substrate transport by Organic Cation Transporter 1. Nature Communications, 14(1). [More Information]
- Nolan, K., Font Sadurni, J., Sresutharsan, A., Gotsbacher, M., Brown, C., Ryan, R., Codd, R. (2022). Acetyl-CoA-Mediated Post-Biosynthetic Modification of Desferrioxamine B Generates N- and N-O-Acetylated Isomers Controlled by a pH Switch. ACS Chemical Biology, 17(2), 426-437. [More Information]
2024
- Nolan, K., Rosser, C., Wood, J., Font Sadurni, J., Sresutharsan, A., Wang, J., Markham, T., Ryan, R., Codd, R. (2024). An elastic siderophore synthetase and rubbery substrates assemble multimeric linear and macrocyclic hydroxamic acid metal chelators. Chemical Science. [More Information]
2023
- Zeng, Y., Sobti, M., Quinn, A., Smith, N., Brown, S., Vandenberg, J., Ryan, R., O'Mara, M., Stewart, A. (2023). Structural basis of promiscuous substrate transport by Organic Cation Transporter 1. Nature Communications, 14(1). [More Information]
2022
- Nolan, K., Font Sadurni, J., Sresutharsan, A., Gotsbacher, M., Brown, C., Ryan, R., Codd, R. (2022). Acetyl-CoA-Mediated Post-Biosynthetic Modification of Desferrioxamine B Generates N- and N-O-Acetylated Isomers Controlled by a pH Switch. ACS Chemical Biology, 17(2), 426-437. [More Information]
- wu, Q., Akhter, A., Pant, S., Cho, E., Zhu, J., Garner, A., Ohyama, T., Tajkhorshid, E., van Meyel, D., Ryan, R. (2022). Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function. Journal of Clinical Investigation, 132(7), e154891. [More Information]
- Freidman, N., Briot, C., Ryan, R. (2022). Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family. Journal of Biological Chemistry, 298(8). [More Information]
2021
- Chen, I., Pant, S., wu, Q., Cater, R., Sobti, M., Vandenberg, R., Stewart, A., Tajkhorshid, E., Font Sadurni, J., Ryan, R. (2021). Glutamate transporters have a chloride channel with two hydrophobic gates. Nature, 591(7849), 327-331. [More Information]
- Aguilar, J., Cheng, M., Font Sadurni, J., Schwartz, A., Ledwitch, K., Duran, A., Mabry, S., Belovich, A., Zhu, Y., Carter, A., Ryan, R., et al (2021). Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia. eLife, 10, e68039-1-e68039-32. [More Information]
- Ryan, R., Ingram, S., Scimemi, A. (2021). Regulation of Glutamate, GABA and Dopamine Transporter Uptake, Surface Mobility and Expression. Frontiers in Cellular Neuroscience, 15, 670346. [More Information]
2020
- Freidman, N., Chen, I., wu, Q., Briot, C., Holst, J., Font Sadurni, J., Vandenberg, R., Ryan, R. (2020). Amino Acid Transporters and Exchangers from the SLC1A Family: Structure, Mechanism and Roles in Physiology and Cancer. Neurochemical Research, 45(6), 1268-1286. [More Information]
2019
- Mostyn, S., Rawling, T., Mohammadi, S., Shimmon, S., Frangos, Z., Sarker, S., Yousuf, A., Vetter, I., Ryan, R., Christie, M., Vandenberg, R. (2019). Development of an N-acyl amino acid that selectively inhibits the glycine transporter 2 to produce analgesia in a rat model of chronic pain. Journal of Medicinal Chemistry, 62(5), 2466-2484. [More Information]
- Mostyn, S., Wilson, K., Schumann-Gillett, A., Frangos, Z., Shimmon, S., Rawling, T., Ryan, R., O'Mara, M., Vandenberg, R. (2019). Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics. eLife, 8, 1-22. [More Information]
2018
- van Geldermalsen, M., Quek, L., Turner, N., Freidman, N., Pang, A., Guan, Y., Krycer, J., Ryan, R., Wang, Q., Holst, J. (2018). Benzylserine inhibits breast cancer cell growth by disrupting intracellular amino acid homeostasis and triggering amino acid response pathways. BMC Cancer, 18(1), 689 - 1-689 - 14. [More Information]
- Zhou, Q., Reekie, T., Abbassi, R., Indurthi Venkata, D., Font Sadurni, J., Ryan, R., Rendina, L., Munoz, L., Kassiou, M. (2018). Flexible Analogues of Azaindole DYRK1A Inhibitors Elicit Cytotoxicity in Glioblastoma Cells. Australian Journal of Chemistry, 71(10), 789-797. [More Information]
- Carland, J., Thomas, M., Mostyn, S., Subramanian, N., O'Mara, M., Ryan, R., Vandenberg, R. (2018). Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2. ACS Chemical Neuroscience, 9(3), 603-614. [More Information]
2017
- Zhou, Q., Phoa, A., Abbassi, R., Hoque, M., Reekie, T., Font Sadurni, J., Ryan, R., Stringer, B., Day, B., Johns, T., Munoz, L., Kassiou, M. (2017). Structural optimization and pharmacological evaluation of inhibitors targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) and CDC-like kinases (CLK) inglioblastoma. Journal of Medicinal Chemistry, 60(5), 2052-2070. [More Information]
- Mostyn, S., Carland, J., Shimmon, S., Ryan, R., Rawling, T., Vandenberg, R. (2017). Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2. ACS Chemical Neuroscience, 8(9), 1949-1959. [More Information]
- Krycer, J., Fazakerley, D., Cater, R., Cooke, K., Naghiloo, S., Burchfield, J., Humphrey, S., Vandenberg, R., Ryan, R., James, D. (2017). The amino acid transporter SLC1A3 is plasma membrane-localised in adipocytes and its activity is insensitive to insulin. FEBS Letters, 591(2), 322-330. [More Information]
2016
- Vandenberg, R., Ryan, R., Broer, S. (2016). Brain transporters: From genes and genetic disorders to function and drug discovery. Neurochemistry International, 98, 1-3. [More Information]
- McIlwain, B., Vandenberg, R., Ryan, R. (2016). Characterization of the Inward- and Outward-Facing Substrate Binding Sites of the Prokaryotic Aspartate Transporter, GltPh. Biochemistry, 55(49), 6801-6810. [More Information]
- Ryan, R., Vandenberg, R. (2016). Elevating the alternating-access model. Nature Structural and Molecular Biology, 23(3), 187-189. [More Information]
2015
- Vinh, N., Devine, S., Munoz, L., Ryan, R., Wang, B., Krum, H., Chalmers, D., Simpson, J., Scammells, P. (2015). Design, Synthesis, and Biological Evaluation of Tetra-Substituted Thiophenes as Inhibitors of p38a MAPK. ChemistryOpen, 4(1), 56-64. [More Information]
- McIlwain, B., Vandenberg, R., Ryan, R. (2015). Transport rates of a glutamate transporter homologue are influenced by the lipid bilayer. Journal of Biological Chemistry, 290(15), 9780-9788. [More Information]
2014
- Vandenberg, R., Ryan, R., Carland, J., Imlach, W., Christie, M. (2014). Glycine transport inhibitors for the treatment of pain. Trends In Pharmacological Sciences, 35(8), 423-430. [More Information]
- Carland, J., Handford, C., Ryan, R., Vandenberg, R. (2014). Lipid Inhibitors of High Affinity Glycine Transporters: Identification of a novel class of analgesics. Neurochemistry International, 73, 211-216. [More Information]
- Wang, Q., Grkovic, T., Font Sadurni, J., Bonham, S., Pouwer, R., Bailey, C., Moran, A., Ryan, R., Rasko, J., Jormakka, M., Holst, J., et al (2014). Monoterpene Glycoside ESK246 from Pittosporum Targets LAT3 Amino Acid Transport and Prostate Cancer Cell Growth. ACS Chemical Biology, 9(6), 1369-1376. [More Information]
2013
- Carland, J., Edington, A., Scopelliti, A., Ryan, R., Vandenberg, R. (2013). Directed Mutagenesis in Structure Activity Studies of Neurotransmitter Transporters. In David Figurski (Eds.), Genetic Manipulation of DNA and Protein - Examples from Current Research, (pp. 167-184). Rijeka: InTech Publishers. [More Information]
- Ryan, R., Boudker, O. (2013). Glutamate Transporter Family. In Gordon C. K. Roberts (Eds.), Encyclopedia of Biophysics, (pp. 893-900). Heidelberg: Springer.
- Vandenberg, R., Ryan, R. (2013). Mechanisms of glutamate transport. Physiological Reviews, 93(4), 1621-1657. [More Information]
2012
- Bastug, T., Heinzelmann, G., Kuyucak, S., Salim, M., Vandenberg, R., Ryan, R. (2012). Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1. PloS One, 7(3), 1-10. [More Information]
2011
- Bailey, C., Ryan, R., Theong, A., Ng, C., King, K., Vanslambrouck, J., Auray-Blais, C., Vandenberg, R., Bröer, S., Rasko, J. (2011). Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. Journal of Clinical Investigation, 121(1), 446-453. [More Information]
- Vandenberg, R., Handford, C., Campbell, E., Ryan, R., Yool, A. (2011). Water and urea permeation pathways of the human excitatory amino acid transporter EAAT1. Biochemical Journal, 439(2), 333-340. [More Information]
2010
- McKinzie, A., Ryan, R., Vandenberg, R. (2010). Site-Directed Mutagenesis in the Study of Membrane Transporters. In Qing Yan (Eds.), Membrane Transporters in Drug Discovery and Development: Methods and Protocols - Methods in Molecular Biology Volume 637, (pp. 277-293). New York: Humana Press. [More Information]
- Ryan, R., Kortt, N., Sirivanta, T., Vandenberg, R. (2010). The position of an arginine residue influences substrate affinity and K+ coupling in the human glutamate transporter, EAAT1. Journal of Neurochemistry, 114(2), 565-575. [More Information]
2009
- Edington, A., McKinzie, A., Reynolds, A., Kassiou, M., Ryan, R., Vandenberg, R. (2009). Extracellular loops 2 and 4 of GLYT2 are required for N-arachidonylglycine inhibition of glycine transport. Journal of Biological Chemistry, 284(52), 36424-36430. [More Information]
- Ryan, R., Compton, E., Mindell, J. (2009). Functional characterization of a Na+-dependent aspartate transporter from Pyrococcus horikoshii. Journal of Biological Chemistry, 284(26), 17540-17548. [More Information]
- Huang, S., Ryan, R., Vandenberg, R. (2009). The Role of Cation Binding in Determining Substrate Selectivity of Glutamate Transporters. Journal of Biological Chemistry, 284(7), 4510-4515. [More Information]
2008
- Vandenberg, R., Huang, S., Ryan, R. (2008). Slips, leaks and channels in glutamate transporters. Channels, 2(1), 51-58. [More Information]
2007
- Boudker, O., Ryan, R., Yernool, D., Shimamoto, K., Gouaux, E. (2007). Coupling substrate and ion binding to extracellular gate of a sodium-dependent aspartate transporter. Nature, 445(7126), 387-393. [More Information]
- Ryan, R., Mindell, J. (2007). The uncoupled chloride conductance of a bacterial glutamate transporter homolog. Nature Structural and Molecular Biology, 14(5), 365-371. [More Information]
2005
- Ryan, R., Vandenberg, R. (2005). A channel in a transporter. Clinical and Experimental Pharmacology and Physiology, 32(1-2), 1-6. [More Information]
- Vandenberg, R., Ryan, R. (2005). How and Why Are Channels in Transporters? Signal Transduction Knowledge Environment, 19(280), pe17. [More Information]
2004
- Vandenberg, R., Ju, P., Aubrey, K., Ryan, R., Mitrovic, A. (2004). Allosteric Modulation Of Neurotransmitter Transporters At Excitatory Synapses. European Journal of Pharmaceutical Sciences, 23(1), 1-11. [More Information]
- Jennings, E., Ryan, R., Christie, M. (2004). Effects Of Sumatriptan On Rat Medullary Dorsal Horn Neurons. Pain, 111(1-2), 30-37. [More Information]
- Ryan, R., Mitrovic, A., Vandenberg, R. (2004). The Chloride Permeation Pathway Of A Glutamate Transporter And Its Proximity To The Glutamate Translocation Pathway. Journal of Biological Chemistry, 279(20), 20742-20751. [More Information]
2003
- Ryan, R., Mitrovic, A., Vandenberg, R. (2003). Site-directed mutagenesis in the study of membrane transportes. In Qing Yan (Eds.), Membrane Transporters: Methods and Protocols (Methods in Molecular Biology Vol. 227), (pp. 97-108). New Jersey, USA: Humana Press.
2002
- Ryan, R., Vandenberg, R. (2002). Distinct conformational states mediate the transport and anion channel properties of the glutamate transporter EAAT-1. Journal of Biological Chemistry, 277(16), 13494-13500. [More Information]
- Borgland, S., Connor, M., Ryan, R., Ball, H., Christie, M. (2002). Prostaglandin E2 inhibits calcium current in two sub-populations of acutely isolated mouse trigeminal sensory neurons. Journal of Physiology, 539(2), 433-444. [More Information]
Selected Grants
2024
- Dedicated High-throughput 3D-Electron Diffractometer, Ling C, Lewis W, Ryan R, Zheng R, Australian Research Council (ARC)/Linkage Infrastructure, Equipment and Facilities (LIEF)
2023
- Rewarding Research 2024, Ryan R, Faculty of Medicine and Health/FMH Rewarding Research Success
- Nanocrystal Electron Diffraction Facility, Kepert C, Ryan R, Australian Research Council (ARC)/Linkage Infrastructure, Equipment and Facilities (LIEF)
- Elucidating the molecular mechanisms of dual function transporter/channels, Ryan R, Australian Research Council (ARC)/Future Fellowships (FT)
In the media
Unlocking the brain’s building blocks – Cosmos Magazine (11 Aug 2023)
Twisty molecular elevator - Cosmos Magazine (18 Feb 2021)
OECD Closed Roundtable on the impact of COVID-19 on women: Spotlight on women in STEM (19 Oct 2020)
STEMM: Seeing how far we have come, how far we have yet to go - OECD Forum 2019 (3 June 2019)
We need disruptive systemic change - Women's Agenda (24 April 2019)
Do you need a mentor? - Frankie Magazine (12 Oct 2018)
The hidden curriculum in surgery says it’s not for women- The Conversation (3 Aug 2016)
The health effects of inhaling nitrous oxide cartridges- Hijacked (9 Oct 2014)
