Handling FMRP and its molecular partners: Structural insights into Fragile X Syndrome

Abstract

Fragile X Mental Retardation Protein (FMRP) is a RNA-binding protein (RBP) known to control different steps of mRNA metabolism, even though its complete function is not fully understood yet. Lack or mutations of FMRP lead to Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and a leading monogenic cause of autism spectrum disorder (ASD). It is well established that FMRP has a multi-domain architecture, a feature that allows this RBP to be engaged in a large interaction network with numerous proteins and mRNAs or non-coding RNAs. Insights into the three-dimensional (3D) structure of parts of its three domains (N-terminus, central domain and C-terminus) were obtained using Nuclear Magnetic Resonance and X-ray diffraction, but the complete 3D arrangement of each domain with respect to the others is still missing. Here, we review the structural features of FMRP and of the network of its protein and RNA interactions. Understanding these aspects is the first necessary step towards the design of novel compounds for new therapeutic interventions in FXS.

Keywords: FMRP; Fragile X syndrome; Neurodevelopmental disease; Protein domains: three-dimensional structure; RNA-Binding protein.