Parkinson’s disease (PD) is the second most common neurodegenerative disorder. PD associated human UCHL1 (Ubiquitin C-terminal hydrolase L1) gene belongs to the family of deubiquitinases and is known to be highly expressed in neurons (1–2% in soluble form). Several functions of UCHL1 have been proposed including ubiquitin hydrolyze activity, ubiquitin ligase activity and stabilization of the mono-ubiquitin. Mutations in human UCHL1 gene have been associated with PD and other neurodegenerative disorders. The present study aims to decipher the sequence evolutionary pattern and structural dynamics of UCHL1. Furthermore, structural and interactional analysis of UCHL1 was performed to help elucidate the pathogenesis of PD. The phylogenetic tree topology suggests that the UCHL1 gene had originated in early gnathostome evolutionary history. Evolutionary rate analysis of orthologous sequences reveals strong purifying selection on UCHL1. Comparative structural analysis of UCHL1 pinpoints an important protein segment spanning amino acid residues 32 to 39 within secretion site with crucial implications in evolution and PD pathogenesis through a well known phenomenon called intragenic epistasis. Identified critical protein segment appears to play an indispensable role in protein stability, proper protein conformation as well as harboring critical interaction sites. Conclusively, the critical protein segment of UCHL1 identified in the present study not only demonstrates the relevant role of intraprotein conformational epistasis in the pathophysiology of PD but also offers a novel therapeutic target for the disease.

中文翻译：

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人类UCHL1基因的分子进化和结构分析证明基因上位上位性在帕金森氏病和其他神经系统疾病中的相关作用

帕金森氏病（PD）是第二常见的神经退行性疾病。与PD相关的人UCHL1（泛素C末端水解酶L1）基因属于去泛素酶家族，已知在神经元中高表达（可溶性形式为1-2％）。已经提出了UCHL1的几种功能，包括泛素水解活性，泛素连接酶活性和单泛素的稳定化。人UCHL1基因的突变与PD和其他神经退行性疾病有关。本研究旨在破译UCHL1的序列进化模式和结构动力学。此外，进行了UCHL1的结构和相互作用分析，以帮助阐明PD的发病机理。系统发育树拓扑表明，UCHL1基因起源于早期的gnathostome进化史。直系同源序列的进化速率分析揭示了对UCHL1的强纯化选择。UCHL1的比较结构分析指出了分泌位点内跨越氨基酸残基32至39的重要蛋白质片段，通过众所周知的基因内上位现象，对进化和PD发病机制具有至关重要的意义。鉴定出的关键蛋白片段似乎在蛋白稳定性，正确的蛋白构象以及具有关键的相互作用位点中起着不可或缺的作用。最后，本研究中确定的UCHL1的关键蛋白片段不仅证明了蛋白内构象上皮在PD的病理生理中的相关作用，而且为该病提供了新的治疗靶标。