De novo-designed transmembrane domains tune engineered receptor functions
- Author(s)
- Elazar, A; Chandler, NJ; Davey, AS; Weinstein, JY; Nguyen, JV; Trenker, R; Cross, RS; Jenkins, MR; Call, MJ; Call, ME; Fleishman, SJ;
- 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
- Research Division(s)
- Structural Biology; Immunology
- PubMed ID
- 35506657
- Publisher's Version
- https://doi.org/10.7554/eLife.75660
- 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