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

ELAV/Hu蛋白包括一个高度保守的RNA结合蛋白家族，主要在神经元中表达，在神经元中发挥调节突触连接的作用，对学习和记忆至关重要。ELAV/Hu蛋白的异常调节与神经退行性疾病如阿尔茨海默病和帕金森病有关。此外，包括胶质母细胞瘤、胰腺癌、结直肠癌和肺癌在内的许多癌症都异常表达ELAV/Hu蛋白，但导致这些疾病的分子机制尚不清楚。RNA结合蛋白结合短基序。然而，这些基序在基因组中是退化的和高度冗余的。它们如何在这样一个退化的序列空间中准确地产生特异性来过滤正确的靶标，目前尚不清楚，但可能包括RNA结合蛋白的组合相互作用。我们发现ELAV/Hu蛋白可以多聚。现在，我们将利用低温电子显微镜构建与RNA结合的多聚体ELAV复合物的结构，并使用果蝇遗传模型测试多聚介导的RNA识别在神经变性和癌症中的作用。

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.