Distinct phases of cellular signaling revealed by time-resolved protein synthesis

Gihoon Lee, Tom W. Muir

Research output: Contribution to journalArticlepeer-review

Abstract

The post-translational regulation of protein function is involved in most cellular processes. As such, synthetic biology tools that operate at this level provide opportunities for manipulating cellular states. Here we deploy proximity-triggered protein trans-splicing technology to enable the time-resolved synthesis of target proteins from premade parts. The modularity of the strategy allows for the addition or removal of various control elements as a function of the splicing reaction, in the process permitting the cellular location and/or activity state of starting materials and products to be differentiated. The approach is applied to a diverse set of proteins, including the kinase oncofusions breakpoint cluster region–Abelson (BCR–ABL) and DNAJ–PKAc where dynamic cellular phosphorylation events are dissected, revealing distinct phases of signaling and identifying molecular players connecting the oncofusion to cancer transformation as new therapeutic targets of cancer cells. We envision that the tools and control strategies developed herein will allow the activity of both naturally occurring and designer proteins to be harnessed for basic and applied research. (Figure presented.)

Original languageEnglish (US)
Pages (from-to)1353-1360
Number of pages8
JournalNature Chemical Biology
Volume20
Issue number10
DOIs
StatePublished - Oct 2024

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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