Engineering allosteric regulation in protein kinases.
Sci Signal
; 11(555)2018 11 06.
Article
em En
| MEDLINE
| ID: mdl-30401787
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Engenharia de Proteínas
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Regulação Enzimológica da Expressão Gênica
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Proteínas Quinases Ativadas por Mitógeno
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Proteínas de Saccharomyces cerevisiae
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Sítio Alostérico
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article