SH2 Domains: Folding, Binding and Therapeutical Approaches

Abstract

SH2 (Src Homology 2) domains are among the best characterized and most studied protein-protein interaction (PPIs) modules able to bind and recognize sequences presenting a phosphorylated tyrosine. This post-translational modification is a key regulator of a plethora of physiological and molecular pathways in the eukaryotic cell, so SH2 domains possess a fundamental role in cell signaling. Consequently, several pathologies arise from the dysregulation of such SH2-domains mediated PPIs. In this review, we recapitulate the current knowledge about the structural, folding stability, and binding properties of SH2 domains and their roles in molecular pathways and pathogenesis. Moreover, we focus attention on the different strategies employed to modulate/inhibit SH2 domains binding. Altogether, the information gathered points to evidence that pharmacological interest in SH2 domains is highly strategic to developing new therapeutics. Moreover, a deeper understanding of the molecular determinants of the thermodynamic stability as well as of the binding properties of SH2 domains appears to be fundamental in order to improve the possibility of preventing their dysregulated interactions.

CRK and NCK adaptors may functionally overlap in zebrafish neurodevelopment, as indicated by common binding partners and overlapping expression patterns

“…Structurally, an important attribute for SH2 domain function is the binding pocket, which can recognize a specific amino acid region in an interacting protein [39]. An SH2 domain's binding to interacting partners is centered around tyrosine and is impingent on phosphorylation of that tyrosine.…”

“…An SH2 domain's binding to interacting partners is centered around tyrosine and is impingent on phosphorylation of that tyrosine. However, the SH2 domain also recognizes other adjacent amino acids near the tyrosine providing specificity to the interaction [39]. To compare SH2 binding motif preference of the SH2 and SH3 domain-containing adaptors, we generated Weblogos [13] of the consensus binding partner motifs based on known SH2 interaction preferences [12,14].…”

High-Throughput profiling of SH2 domains using Affimer reagents: unravelling protein interaction networks

“…The range of clones per target varied from 1-48 (Table 1). As SH2 domains share high structural homology [25], a microarray approach was used to determine the speci city of these binders for their target domain in a rapid fashion. BAP-tagged SH2 domains were printed onto streptavidin coated slides, ve spots for each SH2 domain, 10 buffer spots per array and 14 arrays per slide.…”

RAS‐targeted cancer therapy: Advances in drugging specific mutations

“…Different from PI3K IAs, PI3K IBs are activated by GPCRs. 193 , 194 , 195 Class I PI3Ks are activated through different upstream mechanisms, which mainly contain: (1) the regulatory subunit p85 binding to phospho‐YXXM motifs (X indicates any amino acid) of the RTK, thereby triggering activation of the catalytic subunit p110 196 ; (2) growth factor receptor‐bound protein 2 (GRB2) binding to phospho‐YXN motifs of the RTK in advance and to the scaffolding protein GAB, which in turn can bind to p85 197 ; and (3) GRB2 binding to RTK and subsequently activating SOS, RAS in turn, and finally activating p110 independently of p85. 198 …”