Abstract
LARP4A belongs to the ancient RNA-binding protein superfamily of La-related proteins (LARPs). In humans, it acts mainly by stabilizing mRNAs, enhancing translation and controlling polyA lengths of heterologous mRNAs. These activities are known to implicate its association with mRNA, protein partners and translating ribosomes, albeit molecular details are missing. Here, we characterize the direct interaction between LARP4A, oligoA RNA and the MLLE domain of the PolyA-binding protein (PABP). Our study shows that LARP4A–oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif. Against expectations, we show that the La module, the conserved RNA-binding unit across LARPs, is not the principal determinant for oligoA interaction, only contributing to binding to a limited degree. Furthermore, the variant PABP-interacting motif 2 (PAM2w) featured in the N-terminal region of LARP4A was found to be important for both RNA and PABP recognition, revealing a new role for this protein–protein binding motif. Our analysis demonstrates the mutual exclusive nature of the PAM2w-mediated interactions, thereby unveiling a tantalizing interplay between LARP4A, polyA and PABP.
Highlights
LARP4A is a mainly cytoplasmic protein that promotes mRNA translation and stabilization, 3 UTR polyA lengthening, post-transcriptional regulation of ribosomal protein production and miRNA processing [1,2,3,4]
Our study shows that LARP4A–oligoA association entails novel RNA recognition features involving the N-terminal region of the protein that exists in a semi-disordered state and lacks any recognizable RNA-binding motif
The 3D structure of the La module of human LARP4A was determined using standard heteronuclear multidimensional NMR techniques. These analyses showed that, analogously to other La-related proteins (LARPs), LARP4A La module comprises two independently folded globular domains, the La motif (LaM) and the RRM1, connected by a linker (Figure 1)
Summary
LARP4A is a mainly cytoplasmic protein that promotes mRNA translation and stabilization, 3 UTR polyA lengthening, post-transcriptional regulation of ribosomal protein production and miRNA processing [1,2,3,4] It interacts with poly(A), the PolyA-binding protein (PABP) and the receptor for activated C kinase (RACK1), and associates with translating polyribosomes [1]. While a single LARP4 gene is found in invertebrate species, a gene duplication event very early in the vertebrate lineage gave rise to two variants termed LARP4A/LARP4 and LARP4B/LARP5 [5]. We refer to these proteins as LARP4A and LARP4B . LARP4B has been found to act as a tumour suppressor by a genetic screen in mice and human glioma cells [9,10]
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