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.

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

“…In contrast to the SH2 domain, the SH3 domain is a small domain with 60 residues and is characterized by its ability to bind proline-containing sequences to form polyproline type II helixes [140,141,145]. While most NRTKs possess SH domains, there are also some that lack SH2 and SH3 domains [154,155]. These NRTKs possess some subfamily-specific domains that are essential for protein-protein interactions [156].…”

The Ubiquitin-Associated and SH3 Domain-Containing Proteins (UBASH3) Family in Mammalian Development and Immune Response

“…The UBASH3 family, specifically UBASH3A (previously known as Sts-1) and UBASH3B (previously known as Sts-2), plays crucial roles during mammalian development and immune responses [1]. These proteins contain ubiquitin-associated (UBA) and Src homology 3 (SH3) domains, which are essential for their functions in cellular signalling, particularly in regulating immune cell signalling [2]. Accordingly, they modulate various signalling pathways in immune cells like T-cells, B-cells, and macrophages.…”

Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily

“…Among the diverse array of protein domains that facilitate these interactions, the SRC homology 3 (SH3) domains stand out as central modular units. These compact domains, consisting of approximately 60 amino acids with similar sequences that adopt a compact β-barrel fold made of five β-strands [2], are found predominantly in various signaling proteins and various protein families [3,4]. The selective interactions of the SH3 domain with proline-rich motifs (PRMs) are fundamental for the assembly and orchestration of multiprotein complexes [5].…”

“…The selective interactions of the SH3 domain with proline-rich motifs (PRMs) are fundamental for the assembly and orchestration of multiprotein complexes [5]. It is rational that the SH3 domain-containing proteins (SH3DCPs) are involved in a wide variety of biological processes [4], subsequently leading to a substantial influence on a spectrum of diseases, 2 of 18 such as cancers [6], neurological disorders [7], kidney and urinary disorders [8,9], muscle and myopathy disorders [10,11], immune disorders [12,13], and genetic and developmental disorders [4,14,15].…”

“…The preference of the SH3 domain for specific PRMs is usually moderate, with affinities typically in the low micromolar range [20][21][22]. Furthermore, SH3 domains exhibit a broad spectrum of both conventional (PRM-based) and nonconventional selectivity, effectively recognizing a diverse array of protein interactors in a differentiated manner [4,5].…”