Prof James Murphy, Deputy Director | WEHI Researcher Profile

Q: How does the "dead" enzyme MLKL induce cell death

The pseudokinase, MLKL, is the terminal effector in the necroptosis cell death pathway. Our structural studies and development of MLKL-deficient laboratory models have enabled us to greatly advance mechanistic knowledge of this protein. Our ongoing work is directed toward understanding how MLKL kills cells following its activation by the upstream protein kinase, RIPK3, and the role of this pathway in causing inflammatory diseases and cancer. These studies are highly collaborative and draw upon in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics approaches.

Q: The emerging roles of pseudokinases in disease

We have identified allostery, molecular switch, scaffolding and competition functions for pseudokinases from detailed structural and functional characterization. Many pseudokinases remain understudied and are considered members of the “dark kinome”. Ongoing work seeks to define the biological functions of these proteins, how they misfunction in disease, and establish their candidacy as drug targets to counter human diseases, especially inflammatory and proliferative diseases. Our work is highly collaborative, with integration of in vivo biology, structural biology, molecular and cellular biology, biochemistry, chemical biology and proteomics to dissect their functions.

Q: Structure-function characterisation of the epigenetic regulator, Smchd1

Smchd1 is a poorly understood protein comprising an N-terminal ATPase and C-terminal hinge domain. Our recent studies have sought to understand the biological functions (in collaboration with Prof Marnie Blewitt) and structures (in collaboration with Prof Peter Czabotar) of the component domains with a view to understanding its pleiotropic roles as a tumour suppressor, in X chromosome inactivation and gene imprinting.

About

Our work is focused on understanding how proteins within cells interact, and how genetic mutations that perturb these interactions can cause disease.

We are particularly interested in interactions between proteins involved in cell signalling. The network of signalling proteins within cells can be likened to an electronic circuit. Our research is identifying the missing components in these ‘circuits’ and explaining how diseases are caused by defects in the circuit components.

By understanding how defective signalling causes disease, we aim to develop drugs to control the actions of defective components. In particular we are seeking to understand how signalling defects can lead to a range of diseases, including ischemia-reperfusion injuries, such as stroke and kidney injury, inflammatory bowel disease, muscular dystrophy and cancers.

Education

Joint appointments

Grants and funding

Publications

Selected publications from Prof James Murphy

Horne CR, Dite TA, Young SN, Mather LJ, Dagley LF, Johnson JL, Yaron-Barir TM, Huntsman EM, Daly LA, Byrne DP, Cadell AL, Ng BH, Yousef J, Multari DH, Shen L, McAloon LM, Manning G, Febbraio MA, Means AR, Cantley LC, Tanzer MC, Croucher DR, Eyers CE, Eyers PA, Scott JW, Murphy JM. PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins. Proceedings of the National Academy of Sciences of the United States of America. 2025;122(8):10.1073/pnas.2420961122

Hoblos H, Cawthorne W, Samson AL, Murphy JM. Protein shapeshifting in necroptotic cell death signaling. Trends in Biochemical Sciences. 2025;50(2):10.1016/j.tibs.2024.11.006

Pefanis A, Bongoni AK, McRae JL, Salvaris EJ, Fisicaro N, Murphy JM, Ierino FL, Cowan PJ. Inhibition of RIPK1 or RIPK3 kinase activity post ischemia-reperfusion reduces the development of chronic kidney injury. Biochemical Journal. 2025;482(2):10.1042/bcj20240569

Tye H, Conos SA, Djajawi TM, Gottschalk TA, Abdoulkader N, Kong IY, Kammoun HL, Narayana VK, Kratina T, Speir M, Emery J, Simpson DS, Hall C, Vince AJ, Russo S, Crawley R, Rashidi M, Hildebrand JM, Murphy JM, Whitehead L, De Souza DP, Masters SL, Samson AL, Lalaoui N, Hawkins ED, Murphy AJ, Vince JE, Lawlor KE. Divergent roles of RIPK3 and MLKL in high-fat diet–induced obesity and MAFLD in mice. Life Science Alliance. 2025;8(1):10.26508/lsa.202302446

Chiou S, Cawthorne W, Soerianto T, Hofferek V, Patel KM, Garnish SE, Tovey Crutchfield EC, Hall C, Hildebrand JM, McConville MJ, Lawlor KE, Hawkins ED, Samson AL, Murphy JM. MLKL deficiency elevates testosterone production in male mice independently of necroptotic functions. Cell Death & Disease. 2024;15(11):10.1038/s41419-024-07242-z

Cater RJ, Ryan RM, Oakhill JS, Czabotar P, Murphy JM, Call MJ. Structure, function, surf, repeat: A week at Lorne Proteins 2024. Structure. 2024;32(11):10.1016/j.str.2024.10.007

Maddirevula S, Shagrani M, Ji A-R, Horne CR, Young SN, Mather LJ, Alqahtani M, McKerlie C, Wood G, Potter PK, Abdulwahab F, AlSheddi T, van der Woerd WL, van Gassen KLI, AlBogami D, Kumar K, Muhammad Akhtar AS, Binomar H, Almanea H, Faqeih E, Fuchs SA, Scott JW, Murphy JM, Alkuraya FS. Large-scale genomic investigation of pediatric cholestasis reveals a novel hepatorenal ciliopathy caused by PSKH1 mutations. Genetics in Medicine. 2024;26(11):10.1016/j.gim.2024.101231

Davies KA, Czabotar PE, Murphy JM. Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis. Current Opinion in Structural Biology. 2024;88:10.1016/j.sbi.2024.102891

Garnish SE, Horne CR, Meng Y, Young SN, Jacobsen AV, Hildebrand JM, Murphy JM. Inhibitors identify an auxiliary role for mTOR signalling in necroptosis execution downstream of MLKL activation. Biochemical Journal. 2024;481(17):10.1042/bcj20240255

Diplock N, Baudin M, Xiang X, Liang L-Y, Dai W, Murphy JM, Lucet IS, Hassan JA, Lewis JD. Molecular dissection of the pseudokinase ZED1 expands effector recognition to the tomato immune receptor ZAR1. Plant Physiology. 2024;196(1):10.1093/plphys/kiae268