Proteinas de union a RNA. Regulación de la traducción

Dysregulation of RBPs produce widespread effects, challenging the identification of the molecular mechanisms contributing to disease. GEMIN5 is a predominant cytoplasmic protein, encoded by a single gene, initially known as a member of the survival of the motor neurons (SMN) complex. The protein is also a ribosome binding protein and a translation regulatory factor. GEMIN5 is organized in structural and functional domains, including a WD40 repeats domain, a tetratricopeptide repeat (TPR) dimerization module, and a non-canonical RNA-binding site. The singular organization enables this protein to perform multiple functions through its ability to interact with distinct partners, both RNAs and proteins. Gemin5 is an essential gene, as shown by the detrimental activity of biallelic mutants found in patients, and the embryonic lethal phenotype of Drosophila Rigor mortis. GEMIN5 silencing in human cells revealed that this protein promotes polysome association of selected targets, favoring translation of mRNAs that play a key role in cellular proliferation. Patients carrying Gemin5 biallelic variants, that display cerebellar atrophy, ataxia, cognitive delay, and hypotonia, harbor conformational changes of the dimerization domain. Moreover, detailed molecular and structural studies of GEMIN5 mutants carrying pathological substitutions led us to conclude that the GEMIN5 interactome depends upon its oligomerization capacity.