A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling

Abstract

SRC homology 3 (SH3) domains are fundamental modules that enable the assembly of protein complexes through physical interactions with a pool of proline-rich/noncanonical motifs from partner proteins. They are widely studied modular building blocks across all five kingdoms of life and viruses, mediating various biological processes. The SH3 domains are also implicated in the development of human diseases, such as cancer, leukemia, osteoporosis, Alzheimer's disease, and various infections. A database search of the human proteome reveals the existence of 298 SH3 domains in 221 SH3 domain-containing proteins (SH3DCPs), ranging from 13 to 720 kilodaltons. A phylogenetic analysis of human SH3DCPs based on their multi-domain architecture seems to be the most practical way to classify them functionally, with regard to various physiological pathways. This review further summarizes the achievements made in the classification of SH3 domain functions, their binding specificity, and their significance for various diseases when exploiting SH3 protein modular interactions as drug targets.

Keywords: SH3 domain; SH3 domain-containing proteins; SRC homology 3; proline-rich motifs (PRM); protein interaction; signal transduction.

Figure 1

A representative structure of an SH3 domain PRM complex. A detailed view into the structure (PDB code: 1FYN) of the SH3 domain of FYN tyrosine kinase (left: surface representation; right: ribbon representation; UniProt ID: P06241) in complex with 3BP-2 PR peptide (PAYPPPPVP; orange; UniProt ID: P78314) which shows the characteristic arrangement of beta strands and the PRM-interacting variable loops, referred to as β4-α3₁₀ (magenta), RT (cyan), and hydrophobic patch (W1190) flanked by n-SRC loop (green). Conserved residues that are crucial for the interaction are Y91, Y93, D99, W119, and P134. FYN SH3 shows the typical topology of two perpendicular three-stranded β-sheets and a single turn of α3₁₀.

Figure 2

Schematic diagram of SH3DCPs in diverse signaling pathways. SH3DCPs are crucial signaling proteins, and they include adaptor proteins, kinases, RAS GEFs, RAS GAPs, scaffold proteins, and effectors. They are involved in various signaling processes in the cell. The dashed separation in the figure distinguishes general cellular functions (A) from specific functions in various cell types (B). All information presented in this figure is cited as references in Table S1.

Figure 3

Phylogenetic tree of the SH3DCP superfamily. The tree was generated on the basis of the similarities between domain compositions. The SH3DCP superfamily can be divided into thirteen families, which are marked by different colors of classes at the outer ring.