Novel Roles of SH2 and SH3 Domains in Lipid Binding.

Szabolcs Sipeki,Loretta László,Virag Vas,Anita Kurilla,László Buday,Tamás Takács,Kitti Koprivanacz

doi:10.3390/cells10051191

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.

Highlights

The researchers found that mutational are noticeably smaller structures compared with the lipid-binding sites of pleckstrin homology (PH) domains, destruction of this site reduced PTK6 plasma membrane affinity and localization, tyrosine suggesting the existence of multiple phosphoinositide recognition mechanisms (Figure 2)
Elimination of the supposed phosphatidylinositol-3,4,5-trisphosphate-selective binding site decreased membrane affinity and abolished phosphatidylinositol-3,4,5-trisphosphate sensitivity, while it only reCells 2021, 10, x FOR PEER REVIEW duced the signaling competence in the later minutes upon receptor activation. These results suggest that phosphatidylinositol-3,4,5-trisphosphate engagement via the Src homology 2 (SH2) domain is important for sustained ZAP70 activity but not for activation itself [45]
It has turned out to be important for the insulin-induced phosphotyrosine phosphatase activity of C1-Ten/Tensin2 towards IRS-1. These results show that the recognition of phosphatidylinositol-3,4,5-trisphosphate by the C1-Ten/Tensin2 SH2 domain is essential for the celit is expressed, C1-Ten/Tensin2 is an accepted negative regulator of the Akt/PKB signal transduction pathway, and it inhibits cell survival, proliferation, and migration [56,57]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In the three decades since the first reports that modular protein-binding domains interact with plasma membrane receptors and their downstream effectors, it has been established that such domains are involved in almost every corner of signaling in eukaryotes [1] They allow signaling proteins to assemble into dynamic multiprotein complexes and provide mechanisms to translate one type of intracellular information into other types. They help to convert enzyme-catalyzed chemical modifications of proteins and lipids into alterations in protein–protein interactions and protein subcellular localization [1]. Caskin1—calcium/calmodulindependent serine protein kinase-interacting protein 1; regulates neural synapses biological relevance specific orientation within a membrane-proximal protein complex specific orientation within a membrane-proximal protein complex targeting to membrane subdomains

Many SH2 Domains Themselves Browse Membrane Lipids besides Tyrosine

Visualization

SH3 Domains Function from Constitutive through Regulated Protein Binding to