The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.

Nicole Dölker,Maria W. Górna,Ludovico Sutto,Antonio S. Torralba,Francesco L. Gervasio,Giulio Superti-Furga,Guanghong Wei

doi:10.1371/journal.pcbi.1003863

Abstract

Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.

Highlights

The expression of the constitutively active breakpoint cluster region (BCR)-ABL fusion tyrosine kinase is sufficient for the initiation and maintenance of chronic myelogenous leukemia (CML) in humans [1]
The Abl kinase is a key player in many crucial cellular processes. It is an important anti-cancer drug target, because a mutation leading to the fusion protein Bcr-Abl is the main cause for chronic myeloid leukemia (CML)
There are two main difficulties associated with the development of kinase inhibitors: the high similarity between active sites of different kinases, which makes selectivity a challenge, and mutations leading to resistance, which make it mandatory to search for alternative drugs

Summary

Introduction

The expression of the constitutively active BCR-ABL fusion tyrosine kinase is sufficient for the initiation and maintenance of chronic myelogenous leukemia (CML) in humans [1]. The dysregulated fusion protein activates a number of signaling pathways associated with inhibition of apoptosis and uncontrolled proliferation. In the light of the above it is not surprising that the mechanisms regulating the activation and deactivation of both the wild type cAbl and BCR-ABL tyrosine kinases have attracted a considerable interest [4,5,6,7,8,9]. In physiological conditions the catalytic activity of tyrosine kinases is tightly regulated through the interplay between various protein domains, phosphorylation events and associated conformational states of the catalytic domain (CD) [10]. Its high intrinsic flexibility allows the CD to react to the regulatory elements by switching reversibly between a number of distinct active and inactive states

Methods

Results

Discussion

Conclusion