Novel Roles of SH2 and SH3 Domains in Lipid Binding

Abstract

Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules. It has also been found that particular SH2 and SH3 domains themselves might also bind to and rely on lipids to modulate complex assembly. Some lipid-binding properties of SH2 and SH3 domains are reviewed here.

Sequence-specific targeting of intrinsically disordered protein regions

“…The diversity in binding modes makes it possible to target essentially any unstructured sequence. As highlighted in the case of dynorphin A, our designs induce the target disordered region into the bound structure; such 'induced fit' is a general feature of disordered protein binding interactions in nature 11,35,36 . Diffusion methods can generate binders to targets that can adopt regular secondary structures (helix 8 , strand, and combinations of helix and strand) as the PDB training set is rich in examples of interacting helices and beta strands; our approach covers highly disordered regions with weak secondary structure propensity and where interactions with nearly every residue are important as in the case of polar and charged targets.…”

The RNA-dependent interactions of phosphatidylinositol 4,5-bisphosphate with intrinsically disordered proteins contribute to nuclear compartmentalization

“…Protein domains with ability to bind to PIP2 were selected based on previously published data (69)(70)(71)(72).…”

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance

“…It is notable that the activation of PI3K in many cancer types, including melanoma, is mostly associated with tumor development, progression, and drug resistance [31][32][33][34][35].…”