A combined approach reveals a regulatory mechanism coupling Src's kinase activity, localization, and phosphotransferase-independent functions
- Author(s)
- Ahler, E; Register, AC; Chakraborty, S; Fang, L; Dieter, EM; Sitko, KA; Vidadala, RSR; Trevillian, BM; Golkowski, M; Gelman, H; Stephany, JJ; Rubin, AF; Merritt, EA; Fowler, DM; Maly, DJ;
- Details
- Publication Year 2019-03-25,Volume 74,Issue #2,Page 393-408e.20
- Journal Title
- Molecular Cell
- Publication Type
- Journal Article
- Abstract
- Multiple layers of regulation modulate the activity and localization of protein kinases. However, many details of kinase regulation remain incompletely understood. Here, we apply saturation mutagenesis and a chemical genetic method for allosterically modulating kinase global conformation to Src kinase, providing insight into known regulatory mechanisms and revealing a previously undiscovered interaction between Src's SH4 and catalytic domains. Abrogation of this interaction increased phosphotransferase activity, promoted membrane association, and provoked phosphotransferase-independent alterations in cell morphology. Thus, Src's SH4 domain serves as an intramolecular regulator coupling catalytic activity, global conformation, and localization, as well as mediating a phosphotransferase-independent function. Sequence conservation suggests that the SH4 domain regulatory interaction exists in other Src-family kinases. Our combined approach's ability to reveal a regulatory mechanism in one of the best-studied kinases suggests that it could be applied broadly to provide insight into kinase structure, regulation, and function.
- Publisher
- Cell Press
- Research Division(s)
- Bioinformatics
- PubMed ID
- 30956043
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2019.02.003
- NHMRC Grants
- NHMRC/1054618,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-04-11 12:23:44
Last Modified: 2019-06-26 11:22:59