Chen Yu Wai, Allen Mark D, Veprintsev Dmitry B, Löwe Jan, Bycroft Mark
Centre for Protein Engineering, Medical Research Council Centre, Cambridge, UK.
J Biol Chem. 2004 Jan 30;279(5):3758-65. doi: 10.1074/jbc.M309817200. Epub 2003 Oct 28.
Spinocerebellar ataxia type 1 is a late-onset neurodegenerative disease caused by the expansion of a CAG triplet repeat in the SCA1 gene. This results in the lengthening of a polyglutamine tract in the gene product ataxin-1. This produces a toxic gain of function that results in specific neuronal death. A region in ataxin-1, the AXH domain, exhibits significant sequence similarity to the transcription factor HBP1. This region of the protein has been implicated in RNA binding and self-association. We have determined the crystal structure of the AXH domain of ataxin-1. The AXH domain is dimeric and contains an OB-fold, a structural motif found in many oligonucleotide-binding proteins, supporting its proposed role in RNA binding. By structure comparison with other proteins that contain an OB-fold, a putative RNA-binding site has been identified. We also identified a cluster of charged surface residues that are well conserved among AXH domains. These residues may constitute a second ligand-binding surface, suggesting that all AXH domains interact with a common yet unidentified partner.
1型脊髓小脑共济失调是一种迟发性神经退行性疾病，由SCA1基因中CAG三联体重复序列的扩增引起。这导致基因产物ataxin-1中多聚谷氨酰胺序列延长。这产生了一种毒性功能获得，导致特定神经元死亡。ataxin-1中的一个区域，即AXH结构域，与转录因子HBP1具有显著的序列相似性。该蛋白质区域与RNA结合和自我缔合有关。我们已经确定了ataxin-1的AXH结构域的晶体结构。AXH结构域是二聚体，包含一个OB折叠，这是在许多寡核苷酸结合蛋白中发现的一种结构基序，支持其在RNA结合中的假定作用。通过与其他含有OB折叠的蛋白质进行结构比较，确定了一个假定的RNA结合位点。我们还确定了AXH结构域中一组高度保守的带电荷表面残基。这些残基可能构成第二个配体结合表面，表明所有AXH结构域都与一个共同但尚未确定的伴侣相互作用。
