Computational Modeling of Allosteric Communication Reveals Organizing Principles of Mutation-Induced Signaling in ABL and EGFR Kinases

Abstract

The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic aspects of long-range communications in ABL and EGFR kinases based on the results of multiscale simulations of regulatory complexes and computational modeling of signal propagation in proteins. These approaches have been systematically employed to elucidate organizing molecular principles of allosteric signaling in the ABL and EGFR multi-domain regulatory complexes and analyze allosteric signatures of the gate-keeper cancer mutations. We have presented evidence that mechanisms of allosteric activation may have universally evolved in the ABL and EGFR regulatory complexes as a product of a functional cross-talk between the organizing αF-helix and conformationally adaptive αI-helix and αC-helix. These structural elements form a dynamic network of efficiently communicated clusters that may control the long-range interdomain coupling and allosteric activation. The results of this study have unveiled a unifying effect of the gate-keeper cancer mutations as catalysts of kinase activation, leading to the enhanced long-range communication among allosterically coupled segments and stabilization of the active kinase form. The results of this study can reconcile recent experimental studies of allosteric inhibition and long-range cooperativity between binding sites in protein kinases. The presented study offers a novel molecular insight into mechanistic aspects of allosteric kinase signaling and provides a quantitative picture of activation mechanisms in protein kinases at the atomic level.

Author Summary

Despite recent progress in computational and experimental studies of dynamic regulation in protein kinases, a mechanistic understanding of long-range communication and mechanisms of mutation-induced signaling controlling kinase activity remains largely qualitative. In this study, we have performed a systematic modeling and analysis of allosteric activation in ABL and EGFR kinases at the increasing level of complexity - from catalytic domain to multi-domain regulatory complexes. The results of this study have revealed organizing structural and mechanistic principles of allosteric signaling in protein kinases. Although activation mechanisms in ABL and EGFR kinases have evolved through acquisition of structurally different regulatory complexes, we have found that long-range interdomain communication between common functional segments (αF-helix and αC-helix) may be important for allosteric activation. The results of study have revealed molecular signatures of activating cancer mutations and have shed the light on general mechanistic aspects of mutation-induced signaling in protein kinases. An advanced understanding and further characterization of molecular signatures of kinase mutations may aid in a better rationalization of mutational effects on clinical outcomes and facilitate molecular-based therapeutic strategies to combat kinase mutation-dependent tumorigenesis.