De novo-designed transmembrane domains tune engineered receptor functions
Journal Title
Elife
Abstract
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.
Publisher
eLife
Keywords
CAR T cell; E. coli; Rosetta; chimeric antigen receptor; de novo design; immunology; immunotherapy; inflammation; membrane protein; molecular biophysics; mouse; structural biology; transmembrane
WEHI Research Division(s)
Structural Biology; Immunology
PubMed ID
35506657
Open Access at Publisher's Site
https://doi.org/10.7554/eLife.75660
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2022-05-11 10:40:12
Last Modified: 2022-05-11 11:15:43
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