Department of Gene Therapy, Ulm University, Ulm, Germany.
Department of Neurology, Ulm University, Ulm, Germany.
J Huntingtons Dis. 2022;11(3):227-242. doi: 10.3233/JHD-220543.
Since the discovery of the mutation causing Huntington's disease (HD) in 1993, it has been debated whether an expanded polyglutamine (polyQ) stretch affects the properties of the huntingtin (HTT) protein and thus contributes to the pathological mechanisms responsible for HD. Here we review the current knowledge about the structure of HTT, alone (apo-HTT) or in a complex with Huntingtin-Associated Protein 40 (HAP40), the influence of polyQ-length variation on apo-HTT and the HTT-HAP40 complex, and the biology of HAP40. Phylogenetic analyses suggest that HAP40 performs essential functions. Highlighting the relevance of its interaction with HTT, HAP40 is one of the most abundant partners copurifying with HTT and is rapidly degraded, when HTT levels are reduced. As the levels of both proteins decrease during disease progression, HAP40 could also be a biomarker for HD. Whether declining HAP40 levels contribute to disease etiology is an open question. Structural studies have shown that the conformation of apo-HTT is less constrained but resembles that adopted in the HTT-HAP40 complex, which is exceptionally stable because of extensive interactions between HAP40 and the three domains of HTT. The complex- and to some extent apo-HTT- resists fragmentation after limited proteolysis. Unresolved regions of apo-HTT, constituting about 25% of the protein, are the main sites of post-translational modifications and likely have major regulatory functions. PolyQ elongation does not substantially alter the structure of HTT, alone or when associated with HAP40. Particularly, polyQ above the disease length threshold does not induce drastic conformational changes in full-length HTT. Therefore, models of HD pathogenesis stating that polyQ expansion drastically alters HTT properties should be reconsidered.
自 1993 年发现导致亨廷顿病（HD）的突变以来，人们一直在争论扩展的多聚谷氨酰胺（polyQ）延伸是否会影响亨廷顿蛋白（HTT）的性质，从而有助于导致 HD 的病理机制。在这里，我们回顾了关于 HTT 的结构的当前知识，无论是单独的（apo-HTT）还是与亨廷顿相关蛋白 40（HAP40）形成复合物，polyQ 长度变化对 apo-HTT 和 HTT-HAP40 复合物的影响，以及 HAP40 的生物学。系统发育分析表明，HAP40 具有重要的功能。突出了其与 HTT 相互作用的相关性，HAP40 是与 HTT 共纯化的最丰富的伴侣之一，当 HTT 水平降低时，HAP40 会迅速降解。随着两种蛋白质水平在疾病进展过程中的降低，HAP40 也可能是 HD 的生物标志物。HAP40 水平的下降是否有助于疾病的病因是一个悬而未决的问题。结构研究表明，apo-HTT 的构象受到的限制较少，但类似于在 HTT-HAP40 复合物中采用的构象，由于 HAP40 与 HTT 的三个结构域之间的广泛相互作用，HTT-HAP40 复合物非常稳定。复合物-在某种程度上 apo-HTT-在有限的蛋白水解后抵抗碎片化。apo-HTT 的未解决区域，构成蛋白质的约 25％，是翻译后修饰的主要部位，并且可能具有主要的调节功能。polyQ 延伸不会显著改变 HTT 的结构，无论是单独存在还是与 HAP40 相关联。特别地，超过疾病长度阈值的 polyQ 不会引起全长 HTT 的剧烈构象变化。因此，应该重新考虑指出 polyQ 扩展会严重改变 HTT 性质的 HD 发病机制模型。
