Multimerisation of ELAV/Hu proteins - a key mechanism ensuring specificity for RNA recognition in health and disease

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ELAV/Hu proteins comprise a family of highly conserved RNA binding proteins predominantly expressed in neurons where they have roles in regulating synaptic connectivity important for learning and memory. Aberrant regulation of ELAV/Hu proteins has been linked to neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In addition, a number of cancers aberrantly express ELAV/Hu proteins including glioblastoma, pancreatic, colorectal and lung cancers, but the molecular mechanisms leading to these diseases are not understood.RNA binding proteins bind short motifs. These motifs, however, are degenerate and highly redundant in the genome. How they exactly generate specificity to filter the correct targets in such a degenerate sequence space, is currently not clear, but likely includes combinatorial interactions of RNA binding proteins. We have discovered that ELAV/Hu proteins can multimerize. Now we will employ cryoEM to build a structure for multimeric ELAV complexes bound to RNA and test the role of multimerization mediated RNA recognition in neurodegeneration and cancer using a Drosophila genetic model.