Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hunghom 999077, Hong Kong.
State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hunghom 999077, Hong Kong.
Int J Mol Sci. 2021 Feb 24;22(5):2240. doi: 10.3390/ijms22052240.
The frameshift mutants K192S and R153S, of the polyglutamine tract-binding protein 1 (PQBP-1), are stable intrinsically disordered proteins (IDPs). They are each associated with the severe cognitive disorder known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Relative to the monomeric wild-type protein, these mutants are dimeric, contain more folded contents, and have higher thermal stabilities. Comparisons can be drawn to the toxic oligomerisation in the "conformational diseases", which collectively describe medical conditions involving a substantial protein structural transition in the pathogenic mechanism. At the molecular level, the end state of these diseases is often cytotoxic protein aggregation. The conformational disease proteins contain varying extents of intrinsic disorder, and the consensus pathogenesis includes an early oligomer formation. We reviewed the experimental characterisation of the toxic oligomers in representative cases. PQBP-1 mutant dimerisation was then compared to the oligomerisation of the conformational disease proteins. The PQBP-1 mutants are unique in behaving as stable soluble dimers, which do not further develop into higher oligomers or aggregates. The toxicity of the PQBP-1 mutant dimers lies in the native functions (in transcription regulation and possibly, RNA splicing) being compromised, rather than proceeding to aggregation. Other examples of stable IDP dimers were discussed and we speculated on the roles of IDP dimerisation in protein evolution.
聚谷氨酰胺结合蛋白 1（PQBP-1）的移码突变体 K192S 和 R153S 是稳定的无规卷曲蛋白（IDP）。它们各自与严重的认知障碍有关，称为 Renpenning 综合征，是一种 X 连锁智力障碍（XLID）。与单体野生型蛋白相比，这些突变体是二聚体，含有更多的折叠内容物，热稳定性更高。可以将其与“构象疾病”中的毒性寡聚化进行比较，构象疾病 collectively 描述了在致病机制中涉及大量蛋白质结构转变的医学病症。在分子水平上，这些疾病的最终状态通常是细胞毒性蛋白聚集。构象疾病蛋白含有不同程度的固有无序性，共识发病机制包括早期寡聚体形成。我们回顾了代表性病例中有毒寡聚体的实验特征。然后将 PQBP-1 突变体二聚化与构象疾病蛋白的寡聚化进行了比较。PQBP-1 突变体的独特之处在于它们表现为稳定的可溶性二聚体，不会进一步发展成更高的寡聚体或聚集体。PQBP-1 突变体二聚体的毒性在于其固有功能（转录调节和可能的 RNA 剪接）受损，而不是继续聚集。还讨论了其他稳定 IDP 二聚体的例子，并推测了 IDP 二聚体在蛋白质进化中的作用。
