Fragile X syndrome (FXS) is the most common cause of inherited intellectual impairment and the most frequent single gene cause of autism. FXS results from inactivation of the FMR1 gene resulting in a lack of the FMR1 protein (FMRP). In the absence of FMRP, protein synthesis in the brain is dysregulated, which is thought to be a contributing mechanism in FXS.
Emerging evidence indicates that one function of FMRP is to impede ribosome translocation, thereby reducing the rate of polypeptide elongation during protein synthesis. Therefore, when FMR1 is silenced and FMRP is not made, translation of at least some messenger RNAs (mRNAs) is upregulated, potentially driving some aspects of the syndrome. Determining how FMRP impedes ribosome transit is therefore fundamental to understanding FXS and may be an avenue for therapeutic intervention.
Joel Richter — together with his colleague Andrei Korostelev — plans to investigate how FMRP slows ribosome movement. To do so, they will reconstitute FMRP with ribosomes and other components of the translational machinery and analyze high-resolution structural interactions using cryo-electron microscopy (cryo-EM). These structural assessments will allow Richter and Korostelev to map sites of interaction between FMRP and ribosomes in the presence or absence of mRNA, transfer RNA (tRNA) and translation elongation factors.
By gaining a detailed understanding of interactions between FMRP and the translational machinery, and visualizing the dynamics of such interactions using ensemble cryo-EM, this project will provide essential information about how nascent protein formation can be slowed. Findings from this study may have long-term implications for how certain aspects of FXS could be mitigated by developing therapeutic compounds that mimic the effects of FMRP on ribosome translocation.