Regulatory Roles of the N-Terminal Intrinsically Disordered Region of Modular Src

Abstract

Src, the prototype of Src family kinases (SFKs), is a modular protein consisting of SH4 (SH4) and unique (UD) domains in an N-terminal intrinsically disordered region (IDR), and SH3, SH2, and kinase (KD) folded domains conserved among SFKs. Src functions as a pleiotropic signaling hub in proliferating and post-mitotic cells, and it is related to cancer and neurological diseases. However, its regulatory mechanism is unclear because the existing canonical model is derived from crystallographic analyses of folded constructs lacking the IDR. This work reviews nuclear magnetic resonance analyses of partially structured lipid-binding segments in the flexible UD and the fuzzy intramolecular complex (FIMC) comprising IDR and SH3 domains, which interacts with lipid membranes and proteins. Furthermore, recently determined IDR-related Src characteristics are discussed, including dimerization, SH4/KD intramolecular fastener bundling of folded domains, and the sorting of adhesive structures. Finally, the modulatory roles of IDR phosphorylation in Src activities involving the FIMC are explored. The new regulatory roles of IDRs are integrated with the canonical model to elucidate the functions of full-length Src. This review presents new aspects of Src regulation, and provides a future direction for studies on the structure and function of Src, and their implications for pathological processes.

Ca2+ Signaling and Src Functions in Tumor Cells

“…Figure 3 shows the proposed Ca 2+ -dependent and Ca 2+ -independent CaM-binding sites of human c-Src. However, the proposed Ca 2+ -dependent CaM-binding site at the N-terminus [39] (as reviewed in [40]) is not shown in Figure 3, as the crystallographic structure of the N-terminus of c-Src was missing in this structure. A phylogenetic analysis demonstrated that the two proposed atypical IQ-like CaM-binding sites [43] and the Ca 2+dependent CaM-binding site [37] of c-Src, were fully or highly conserved in vertebrates (as reviewed in [26]).…”

“…The N-terminus of c-Src, where myristoylation and palmitoylation occurs in order to anchor the protein to the plasma membrane, was also proposed as a site where CaM binds to the kinase in a Ca 2+ -dependent mode [39] (as reviewed in [40]). Also, it was demonstrated that myristoylation contributed to the binding of Ca 2+ /CaM to v-Src, as shown using a peptide corresponding to its N-terminus [41].…”

Protein structure–function continuum model: Emerging nexuses between specificity, evolution, and structure

“…Similarly, functions of SNARE (N‐ethylmaleimide‐sensitive factor (NSF) attachment protein (SNAP) receptor) in various forms of the intracellular membrane trafficking responsible for the membrane and biocargo shuffling between multiple compartments within the cell and extracellular environment are dependent on the self‐assembly of its IDRs (Khvotchev & Soloviev, 2022). Disordered regions found in the modular nonreceptor protein tyrosine kinase Src (the prototype of Src family kinases, SFKs) are crucial for interaction of this mediator of pleiotropic molecular signaling with lipid membranes and proteins (Kato, 2022). IDRs play crucial roles in remodeling of the plasma membrane by the surface‐bound protein monomers and oligomers (Araya et al, 2022).…”

Role of c-Src in Carcinogenesis and Drug Resistance

“…However, Perez et al demonstrated that the UD binds acidic lipids and phosphoinositides through its unique lipid-binding region. This interaction is controlled by the phosphorylation of amino acid residues (T37, S75, and S17) in the UD [ 60 ]. The binding of acidic lipids to the UD triggers the displacement of the protein core from the cell membrane.…”