Prof Matt Call, Lab Head | WEHI Researcher Profile

Q: Tuning CAR T-cell potency with de novo designed receptor transmembrane domains

With collaborator Sarel Fleishman (Weizmann Institute of Science, Israel), we have developed and validated a panel of de novo designed transmembrane domains (TMDs) that form stable and specific monomeric, dimeric, trimeric and tetrameric structures in cell membranes. We used these to enforce the corresponding oligomeric states in second-generation chimeric antigen receptors (CARs) against the solid tumour antigen HER2 and showed that both tumour control and cytokine production scaled in direct proportion to the designed oligomeric structure of the TMD (see eLife 2022). Ongoing work in this program is focused on (1) expanding our panel of available TMD sequences and structures, (2) testing the clinical relevance of these new tools for optimising the safety/efficacy profiles of cellular immunotherapies in specific cancer contexts and (3) developing even more sophisticated applications for these sequences in the cellular immunotherapy space. Project resources:'Goldilocks' treatment window could lead to cancer therapy without harmful side-effects [https://www.wehi.edu.au/news/goldilocks-treatment-window-could-lead-cancer-therapy-without-harmful-side-effects]

Q: Understanding the mechanisms of type-I cytokine receptor activation

Homodimeric type I cytokine receptors for growth hormone, erythropoietin and thrombopoietin (GHR, EpoR, TpoR) control processes essential to human health such as tissue growth, regeneration and blood cell production. Impaired activation and/or signalling of these receptors can lead to various pathological conditions, including blood pathologies, cancers, developmental and metabolic disorders. GHR, EpoR, TpoR transmit signals by forming specific structures in their transmembrane domains (TM), though the identities of active and inactive orientations are not well understood. Our laboratory utilizes deep mutational scanning methods coupled to next-generation sequencing to evaluate how a large number of mutations in these receptors’ TM and flanking regions affects their function. Project resources:Genetic cause of blood disease found [https://www.wehi.edu.au/news/genetic-drivers-myeloproliferative-diseases-revealed]

About

I completed my PhD in Immunology at Harvard Medical School and the Dana-Farber Cancer Institute (Boston, MA, USA) and completed postdoctoral training in solution NMR of membrane proteins at Harvard Medical School. I then established an independent research program at WEHI in Melbourne in 2010. My lab has a particular focus on how the membrane-embedded portions of receptors (transmembrane domains) contribute to the structure and function of immune-signalling complexes and other important cellular receptors. These are not mere anchors for extracellular and intracellular domains, but in fact they provide a unique platform for molecular interactions and represent the only direct physical link between ligand-binding and signalling domains across the cell barrier.

We combine biochemical and biophysical methods (both X-ray crystallography and solution NMR) with protein engineering, saturating mutagenesis and cellular and molecular immunology techniques to study the mechanics of receptor activation and the regulation of cell-surface proteins in the immune system. A major focus in recent years has been the development (with computational protein design collaborators) and structural characterisation of synthetic transmembrane domains as tools to control the structures and activities of engineered receptors such as chimeric antigen receptors (CARs) for cellular immunotherapies.

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Selected publications from Prof Matt Call

Chandler NJ, Davey AS, Elazar A, Weinstein JY, Nguyen JV, Trenker R, Cross RS, Jenkins MR, Call ME, Fleishman SJ, Call MJ. De novo -designed transmembrane domains tune chimeric antigen receptor function. Acta Crystallographica Section A: Foundations and advances. 2023;79(a2):10.1107/s2053273323086722

Ramesh S, Park S, Im W, Call MJ, Call ME. T cell and B cell antigen receptors share a conserved core transmembrane structure. Proceedings of the National Academy of Sciences of the United States of America. 2022;119(48):10.1073/pnas.2208058119

Elazar A, Chandler NJ, Davey AS, Weinstein JY, Nguyen JV, Trenker R, Cross RS, Jenkins MR, Call MJ, Call ME, Fleishman SJ. De novo-designed transmembrane domains tune engineered receptor functions. eLife. 2022;11:10.7554/elife.75660

Trenker R, Wu X, Nguyen JV, Wilcox S, Rubin AF, Call ME, Call MJ. Human and viral membrane–associated E3 ubiquitin ligases MARCH1 and MIR2 recognize different features of CD86 to downregulate surface expression. Journal of Biological Chemistry. 2021;297(1):10.1016/j.jbc.2021.100900

Davey AS, Call ME, Call MJ. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers. 2020;13(1):10.3390/cancers13010038

Ramesh S, Park S, Call MJ, Im W, Call ME. Experimentally Guided Computational Methods Yield Highly Accurate Insights into Transmembrane Interactions within the T Cell Receptor Complex. The Journal of Physical Chemistry B. 2020;124(46):10.1021/acs.jpcb.0c06403

Chandler NJ, Call MJ, Call ME. T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors. International Journal of Molecular Sciences. 2020;21(19):10.3390/ijms21197424

Bridgford JL, Lee SM, Lee CMM, Guglielmelli P, Rumi E, Pietra D, Wilcox S, Chhabra Y, Rubin AF, Cazzola M, Vannucchi AM, Brooks AJ, Call ME, Call MJ. Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning. Blood. 2020;135(4):10.1182/blood.2019002561

Brooks A, Campos L, Lee C, Chhabra Y, Bridgford J, Lee SM, Zenatti P, Pissinato L, Rodrigues G, Artico L, Guimarães T, Archangelo L, Martínez L, Slape C, Call M, Call M, Yunes J. THE MECHANISM OF ONCOGENIC MUTATIONS IN THE JUXTAMEMBRANE AND TRANSMEMBRANE REGION OF IL7RA AND TPOR/MPL. Experimental Hematology. 2019;76:10.1016/j.exphem.2019.06.332

van ‘t Hag L, de Campo L, Tran N, Sokolova A, Trenker R, Call ME, Call MJ, Garvey CJ, Leung AE, Darwish TA, Krause-Heuer A, Knott R, Meikle TG, Drummond CJ, Mezzenga R, Conn CE. Protein-Eye View of the in Meso Crystallization Mechanism. Langmuir. 2019;35(25):10.1021/acs.langmuir.9b00647

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Lab research projects

Tuning CAR T-cell potency with de novo designed receptor transmembrane domains

Understanding the mechanisms of type-I cytokine receptor activation

Student research projects

Deep mutational scanning to characterise MLKL’s killer 4HB domain

Graduate Research Masters/Honours/Masters by Coursework/PhD

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Deep mutational scanning to characterise MLKL’s killer 4HB domain

Graduate Research Masters/Honours/Masters by Coursework/PhD

More information

View all student research projects

Prof Matt Call

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