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De novo designed transmembrane domains tune engineered receptor functions

By Assaf Elazar, Nicholas J Chandler, Ashleigh S Davey, Jonathan Y Weinstein, Julie V Nguyen, Raphael Trenker, Ryan R Cross, Misty R Jenkins, Melissa J Call, Matthew E Call, Sarel Jacob Fleishman

Posted 26 Jul 2020
bioRxiv DOI: 10.1101/2020.07.26.221598

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 -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) and found that both CAR T cell cytokine release and in vivo antitumor activity scaled linearly with the oligomeric state encoded by the receptor TMD. All programmed CARs (proCARs) stimulated substantially lower T cell cytokine release relative to the commonly used CD28 TMD, which we show elevated cytokine release through lateral recruitment of 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.

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