Polyglutamine Repeats Are Associated to Specific Sequence Biases That Are Conserved among Eukaryotes

Nine human neurodegenerative diseases, including Huntington's disease and several spinocerebellar ataxia, are associated to the aggregation of proteins comprising an extended tract of consecutive glutamine residues (polyQs) once it exceeds a certain length threshold. This event is believed to be the consequence of the expansion of polyCAG codons during the replication process. This is in apparent contradiction with the fact that many polyQs-containing proteins remain soluble and are encoded by invariant genes in a number of eukaryotes. The latter suggests that polyQs expansion and/or aggregation might be counter-selected through a genetic and/or protein context. To identify this context, we designed a software that scrutinize entire proteomes in search for imperfect polyQs. The nature of residues flanking the polyQs and that of residues other than Gln within polyQs (insertions) were assessed. We discovered strong amino acid residue biases robustly associated to polyQs in the 15 eukaryotic proteomes we examined, with an over-representation of Pro, Leu and His and an under-representation of Asp, Cys and Gly amino acid residues. These biases are conserved amongst unrelated proteins and are independent of specific functional classes. Our findings suggest that specific residues have been co-selected with polyQs during evolution. We discuss the possible selective pressures responsible of the observed biases.

9种人类神经退行性疾病（包括亨廷顿病（Huntington's disease）及多种脊髓小脑共济失调（spinocerebellar ataxia））与蛋白质聚集密切相关，这类蛋白质含有长度超过特定阈值的连续谷氨酰胺残基（glutamine residues）延伸片段，即多聚谷氨酰胺（polyQs）。该现象被认为是复制过程中多聚CAG密码子（polyCAG codons）扩增的结果。而这一结论与下述事实看似矛盾：在多种真核生物（eukaryotes）体内，诸多携带多聚谷氨酰胺的蛋白质始终保持可溶性，且其编码基因未发生变异。上述现象提示，多聚谷氨酰胺的扩增与（或）聚集可能会通过遗传及（或）蛋白质环境受到负向选择。为阐明这一调控背景，我们开发了一款软件，用于全面分析整个蛋白质组（proteome）以搜寻不完全型多聚谷氨酰胺序列。研究人员对多聚谷氨酰胺侧翼的氨基酸残基性质，以及多聚谷氨酰胺序列内非谷氨酰胺的残基（即插入序列）的性质进行了评估。我们在所分析的15种真核生物蛋白质组中，发现了与多聚谷氨酰胺显著相关的强烈氨基酸残基偏好性：脯氨酸（Pro）、亮氨酸（Leu）与组氨酸（His）的占比显著升高，而天冬氨酸（Asp）、半胱氨酸（Cys）与甘氨酸（Gly）的占比显著降低。这些偏好性在无关蛋白质中保持保守，且与蛋白质的特定功能类别无关。本研究结果表明，在进化过程中，特定氨基酸残基与多聚谷氨酰胺发生了共选择。我们对导致上述偏好性产生的潜在选择压力进行了探讨。