De novo-designed transmembrane domains tune engineered receptor functions
| Autor: | Ashleigh S Davey, Nicholas J Chandler, Assaf Elazar, Jonathan Y Weinstein, Julie V Nguyen, Raphael Trenker, Ryan S Cross, Misty R Jenkins, Melissa J Call, Matthew E Call, Sarel J Fleishman |
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| Rok vydání: | 2022 |
| Předmět: |
60199 Biochemistry and Cell Biology not elsewhere classified
Receptors Chimeric Antigen General Immunology and Microbiology T-Lymphocytes General Neuroscience Receptors Antigen T-Cell General Medicine Xenograft Model Antitumor Assays General Biochemistry Genetics and Molecular Biology Mice CD28 Antigens Protein Domains FOS: Biological sciences Animals Cytokines |
| DOI: | 10.26181/19972259 |
| Popis: | De novo-designed receptor transmembrane domains (TMDs) present opportunities for precise control of cellular receptor functions. We developed a de novo design strategy for generating programmed membrane proteins (proMPs): single-pass α-helical TMDs that self-assemble through computationally defined and crystallographically validated interfaces. We used these proMPs to program specific oligomeric interactions into a chimeric antigen receptor (CAR) that we expressed in mouse primary T cells and found that both in vitro CAR T cell cytokine release and in vivo antitumor activity scaled linearly with the oligomeric state encoded by the receptor TMD, from monomers up to tetramers. All programmed CARs stimulated substantially lower T cell cytokine release relative to the commonly used CD28 TMD, which we show elevated cytokine release through lateral recruitment of the endogenous T cell costimulatory receptor CD28. Precise design using orthogonal and modular TMDs thus provides a new way to program receptor structure and predictably tune activity for basic or applied synthetic biology. |
| Databáze: | OpenAIRE |
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