Structural, biological, and biomedical implications of mRNA interactions with the master regulator HuR

Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein (RBP) that has been implicated in a vast range of biological processes including stress response, angiogenesis, cell proliferation, and differentiation. Dysregulation of HuR has been linked to a number of pathological disorders including vascular disease, inflammation, and cancers such as those of the breast and colon. Like many RBPs, HuR is composed of multiple RNA-recognition motif (RRM) domains; however, HuR and the three other members of the Hu family (HuB, HuC, and HuD) possess a unique structural composition with two RRMs separated from a third C-terminal RRM by a long, unstructured hinge region. While there has been extensive research on the role of HuR in cellular, molecular, and developmental biology, there are fewer structural and biochemical studies of HuR and many questions still remain about the molecular mechanisms of HuR. In this review, we endeavor to synthesize existing HuR research spanning the last three decades in order to define known mechanistic roles of each domain, highlight remaining uncertainties, and provide a backdrop for ongoing research into the chemistry and biology of HuR and similar multi-RRM containing proteins.