The Src module: an ancient scaffold in the evolution of cytoplasmic tyrosine kinases

Abstract

Tyrosine kinases were first discovered as the protein products of viral oncogenes. We now know that this large family of metazoan enzymes includes nearly one hundred structurally diverse members. Tyrosine kinases are broadly classified into two groups: the transmembrane receptor tyrosine kinases, which sense extracellular stimuli, and the cytoplasmic tyrosine kinases, which contain modular ligand-binding domains and propagate intracellular signals. Several families of cytoplasmic tyrosine kinases have in common a core architecture, the "Src module," composed of a Src-homology 3 (SH3) domain, a Src-homology 2 (SH2) domain, and a kinase domain. Each of these families is defined by additional elaborations on this core architecture. Structural, functional, and evolutionary studies have revealed a unifying set of principles underlying the activity and regulation of tyrosine kinases built on the Src module. The discovery of these conserved properties has shaped our knowledge of the workings of protein kinases in general, and it has had important implications for our understanding of kinase dysregulation in disease and the development of effective kinase-targeted therapies.

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

“…domains ( Fig. 1B) (27)(28)(29)(30)(31)(32). A feature that distinguishes Btk and other Tec family members from other cytoplasmic tyrosine kinases is the PH-TH module, which consists of a PH domain fused to a zinc-bound Tec homology (TH) domain.…”

Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms

“…While recent studies provided considerable insight on how Btk is autoinhibited, 412little is known about the interdomain rearrangements coordinating Btk activation 413(Shah et al, 2018). Here, we demonstrated that an unsuspected allosteric 414 interaction between the Btk SH2 and KD is critical for kinase activation thereby 415 explaining the loss-of-function phenotype of a subset of XLA mutations in the 416 SH2 domain.…”

Nuclear Functions of the Tyrosine Kinase Src

“…Among them, Src, Yes, and Fyn are expressed in mammals in a ubiquitous manner, while the expression pattern of the other members is tissue and/or cell restricted [2]. These SFKs share high homologous structure consisting of four consecutive Src Homology (SH) domains: an SH4 membrane-targeting region at their N-terminus, that can be myristoylated and/or palmitoylated to allow membrane localization; an intrinsically disordered unique domain, which exhibit strong sequence divergence among SFK members; the regulatory SH-2 and SH-3 domains precede a large catalytic C-terminal domain (SH1) with the hallmark of Src kinases, an autoinhibitory phosphorylation site that is the Y527 residue in human Src (Figure 1) [3].…”

“…All members of the Src family kinases present with myristoylation at the N-terminus [3]. Myristoylation is an irreversible modification that occurs cotranslationally and is catalyzed by the N-myristoyl transferases (NMTs).…”

“…The function of SH2 domain is to specifically bind a target protein by its phosphorylated tyrosine residue within a longer peptide motif, thus allowing SH2 domain-containing proteins to interact. The recognition of the phospho-tyrosine residues within the SH2 domain is guaranteed by a universally conserved arginine residue needed to form the proper electrostatic interactions with the phosphorylated tyrosine [3]. The SH3 domain is crucial for protein-protein interaction by mediating assembly of specific protein complexes, typically via binding to proline-rich peptides bearing the 'PxxP' motif in their respective binding partner [9].…”