Unknown

Dataset Information

0

Engineering allosteric regulation in protein kinases.


ABSTRACT: Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consensus phosphorylation sites at these hotspots, we rewired cell signaling in yeast. Using the same approach with a homolog yeast mitogen-activated protein kinase, Hog1, we introduced new phosphoregulation that modified its localization and signaling dynamics. Beyond revealing potential use in synthetic biology, our findings suggest that the identified hotspots contribute to the diversity of natural allosteric regulatory mechanisms in the eukaryotic kinome and, given that some are mutated in cancers, understanding these hotspots may have clinical relevance to human disease.

SUBMITTER: Pincus D 

PROVIDER: S-EPMC6662207 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

altmetric image

Publications

Engineering allosteric regulation in protein kinases.

Pincus David D   Pandey Jai P JP   Feder Zoë A ZA   Creixell Pau P   Resnekov Orna O   Reynolds Kimberly A KA  

Science signaling 20181106 555


Phosphoregulation, in which the addition of a negatively charged phosphate group modulates protein activity, enables dynamic cellular responses. To understand how new phosphoregulation might be acquired, we mutationally scanned the surface of a prototypical yeast kinase (Kss1) to identify potential regulatory sites. The data revealed a set of spatially distributed "hotspots" that might have coevolved with the active site and preferentially modulated kinase activity. By engineering simple consens  ...[more]

Similar Datasets

| S-EPMC10089111 | biostudies-literature
| S-EPMC4568647 | biostudies-literature
| S-EPMC5340122 | biostudies-literature
| S-EPMC4358782 | biostudies-literature
| S-EPMC3395594 | biostudies-literature
| S-EPMC5286527 | biostudies-literature
| S-EPMC4373616 | biostudies-literature
| S-EPMC7700312 | biostudies-literature
| S-EPMC6911049 | biostudies-literature
| S-EPMC3269071 | biostudies-literature