Products Cited in Publications Worldwide Programmable protein ligation on cell surfaces

Programmable protein ligation on cell surfaces

Kofoed, Christian; Erkalo, Girum; Tay, Nicholas ES; Ye, Xuanjia; Lin, Yutong; Muir, Tom W

DOI: PMID:

Abstract

The surface landscapes of cells difer as a function of cell type and are frequently altered in disease contexts1–3. Exploiting such diferences is key to many therapeutic strategies and is the basis for developing diagnostic and basic-science tools. State-of-the-art strategies typically target single surface antigens, but each individual receptor rarely defnes the specifc cell type4,5. The development of programmable molecular systems that integrate multiple cell-surface features to convert on-target inputs to user-defned outputs is therefore highly desirable. Here we describe an autonomous decision-making device driven by proximity-gated protein trans-splicing that allows local generation of an active protein from two otherwise inactive polypeptide fragments. We show that this protein-actuator platform can perform convergent protein ligation on designated cell surfaces, allowing highly selective generation of active proteins, which can either remain physically associated with the cell surface on which they were manufactured or be released into the surrounding milieu. Because of its intrinsic modularity and tunability, we demonstrate that the technology is compatible with diferent types of input, targeting modality and functional output, allowing for the localized interrogation or manipulation of cellular systems.

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