Strategies for Engineering and Rewiring Kinase Regulation. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: McCormick, James W.; Pincus, David; Resnekov, Orna; Reynolds, Kimberly A.
• Is Part Of: Trends in biochemical sciences. Volume 45:Issue 3(2020)
• Page Start: 259
• Page End: 271
• Publication Date: 2020-03
• Subjects: allostery -- optogenetics -- kinase -- coevolution -- sector -- phosphoregulation; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2019.11.005
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Eukaryotic protein kinases (EPKs) catalyze the transfer of a phosphate group onto another protein in response to appropriate regulatory cues. In doing so, they provide a primary means for cellular information transfer. Consequently, EPKs play crucial roles in cell differentiation and cell-cycle progression, and kinase dysregulation is associated with numerous disease phenotypes including cancer. Nonnative cues for synthetically regulating kinases are thus much sought after, both for dissecting cell signaling pathways and for pharmaceutical development. In recent years advances in protein engineering and sequence analysis have led to new approaches for manipulating kinase activity, localization, and in some instances specificity. These tools have revealed fundamental principles of intracellular signaling and suggest paths forward for the design of therapeutic allosteric kinase regulators. Highlights: Natural kinases are highly regulated by a diversity of mechanisms to ensure that activation occurs at the appropriate time and place. Recent work has developed numerous strategies for engineering new kinase regulation, including controlling upstream signaling, manipulating kinase localization and association, sterically blocking the active site, and introducing novel allosteric control. Light-based (optogenetic) regulation of kinases has been extended across the UV, visible, and infrared spectrum, allowing combinatorial regulatory inputs. Structure-based design and sequence based coevolutionary analyses have emerged as productive strategies for identifying kinase surface sites with allosteric potential. Kinase substrate specificity can be reprogrammed in cases where the recognition motif is well characterized.