We have a particular focus on how the transmembrane domains of receptors contribute to the structure and function of immune-signalling complexes. These are not mere anchors for extracellular and intracellular domains, but provide a unique platform for molecular interactions and represent the only direct physical link between ligand-binding and signalling domains across the cell barrier.

To understand how receptors are activated and the interactions the make with other proteins we are using deep-mutational scanning to uncover mechanistic insights, such as which areas of the protein are susceptible to disease-causing mutations and how to these relate to the natural function of the receptor. A major focus in recent years has been the development (with computational protein design collaborators) and structural characterisation (by x-ray crystallography) of synthetic transmembrane domains as tools to control the structures and activities of engineered receptors such as chimeric antigen receptors for CAR T-cell immunotherapies.

During the pandemic we pivoted some of our research towards understanding how SARS-CoV-2 will respond to therapeutics targeting the viral proteases required for SARS-CoV-2 replication. Our research will predict viral escape mutants before they are observed in the clinic and provide deeper mechanistic insight into Mpro and PLpro function.


Selected publications from A/Prof Melissa Call

Elazar A*, Chandler NJ*, Davey AS*, Weinstein JV, 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:e75660, PMID: 35506657​

Davey AS, Call ME, Call MJ. The Influence of Chimeric Antigen Receptor Structural Domains on Clinical Outcomes and Associated Toxicities. Cancers (Basel). 2020 Dec 25;13(1):38. doi: 10.3390/cancers13010038. PMID: 33375550

Krshnan L, Park S, Im W, Call MJ, Call ME. A conserved αβ transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane. Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):E6649-E6658. doi: 10.1073/pnas.1611445113. Epub 2016 Oct 10. PMID: 27791034

Pos W, Sethi DK, Call MJ, Schulze MS, Anders AK, Pyrdol J, Wucherpfennig KW. Crystal structure of the HLA-DM-HLA-DR1 complex defines mechanisms for rapid peptide selection. Cell. 2012 Dec 21;151(7):1557-68. doi:10.1016/j.cell.2012.11.025. PMID: 23260142

Call MJ, Xing X, Cuny GD, Seth NP, Altmann DM, Fugger L, Krogsgaard M, Stein RL, Wucherpfennig KW. In vivo enhancement of peptide display by MHC class II molecules with small molecule catalysts of peptide exchange. J Immunol. 2009 May 15;182(10):6342-52. doi: 10.4049/jimmunol.0803464.PMID: 19414787

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. J Biol Chem 2021. 297:100900, PMID: 34157285.

Bridgford J, 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. 135:287-289, PMID: 31697803

Trenker R, Call ME, Call MJ. Crystal Structure of the Glycophorin A Transmembrane Dimer in Lipidic Cubic Phase. Journal of the American Chemical Society 2015. 137, 15676-15679 PMID: 26642914

Calleja DJ, Kuchel N, Lu BGC, Birkinshaw RW, Klemm T, Doerflinger M, Cooney JP, Mackiewicz L, Au AE, Yap YQ, Blackmore TR, Katneni K, Crighton E, Newman J, Jarman KE, Call MJ, Lechtenberg BC, Czabotar PE, Pellegrini M, Charman SA, Lowes KN, Mitchell JP, Nachbur U, Lessene G, Komander D. Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Front Chem. 2022 Apr 12;10:861209. doi: 10.3389/fchem.2022.861209. eCollection 2022.PMID: 35494659

Gruszczyk J, Kanjee U, Chan LJ, Menant S, Malleret B, Lim NTY, Schmidt CQ, Mok YF, Lin KM, Pearson RD, Rangel G, Smith BJ, Call MJ, Weekes MP, Griffin MDW, Murphy JM, Abraham J, Sriprawat K, Menezes MJ, Ferreira MU, Russell B, Renia L, Duraisingh MT, Tham WH. Transferrin receptor 1 is a reticulocyte-specific receptor for Plasmodium vivax. Science. 2018 Jan 5;359(6371):48-55. doi: 10.1126/science.aan1078. PMID: 29302006

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