Sequence space exploration in SHP2: mechanistic insights from disease-associated mutations

Abstract

Multi-domain signaling proteins are regulatable switches that mediate signal transduction with high fidelity and selectivity in response to diverse cues. These proteins often harbor disease-associated mutations that disrupt their regulatory properties or interaction specificity to drive pathogenic signaling. Mapping sequence–structure–function relationships in multi-domain signaling proteins is critical to understanding signaling pathways in both healthy and disease states. The protein tyrosine phosphatase SHP2 is a multi-domain protein that can serve as a model system to dissect the molecular basis of signal transduction: SHP2 combines catalytic activity with several binding sites and domains, integrates a variety of inputs, yields a diverse array of potential downstream outcomes, and has extensive interdomain interactions that regulate both its catalytic activity and scaffolding properties. Moreover, numerous mutations have been identified in SHP2 in a variety of human diseases. In the present review, we discuss the myriad ways in which disease-associated mutations perturb SHP2 structure and function. An emerging theme is that pathogenic signaling and disease type are not exclusively determined by mutation-dependent changes in catalytic activity. Rather, SHP2 pathogenicity is driven by changes to its conformational ensemble, which can perturb both catalytic activity and protein–protein interactions. However, these two functional attributes are sometimes differentially affected by mutations, which gives rise to a large diversity of pathogenic outcomes. At the end of the present review, we discuss several open questions and future research directions for understanding SHP2 and multi-domain signaling proteins more broadly.