Abstract:

Microtubule motors play a central role in mRNA trafficking in many systems. However, it is unclear how mRNAs are recruited to the transport machinery and how motor activity is regulated within ribonucleoprotein particles (RNPs). I will present our efforts to address these questions using two experimental models: early Drosophila development and human cancer cells. High-resolution cryo-EM structures of the Drosophila RNA adaptor Egalitarian (Egl) complexed with the dynein motor activator Bicaudal-D (BicD) and three double-stranded RNA targets reveal the basis of mRNA recognition in this system. These structures also show that each adaptor complex associates with two RNA stem-loops. We show using single-molecule resolution in vitro motility assays that docking of two stem-loops is a prerequisite for overcoming BicD autoinhibition and switching on dynein movement, a finding rationalised by Alphafold-assisted structural modelling. These observations suggest the existence of a co-incidence detection mechanism that restricts motor movement until a bona fide mRNA cargo is engaged. I will also present evidence that the RNA-binding proteins FXR1 and FXR2 play an analogous role to Egl during dynein-based mRNP transport in human cells. FXR1 and

FXR2 associate directly with the BicD family member, BICD2, and enable its dynein-activating functions. Collectively, our work reveals similar organisational principles of mRNA transport complexes in divergent eukaryotic cell types, with the RNA cargo determined by the specificity of interchangeable RNA-binding proteins.

 

Hosted by Dek Woolfson & Mark Dodding