Ponts Nadia, Yang Jianfeng, Chung Duk-Won Doug, Prudhomme Jacques, Girke Thomas, Horrocks Paul, Le Roch Karine G
Department of Cell Biology and Neurosciences, University of California at Riverside, Riverside, California, United States of America.
PLoS One. 2008 Jun 11;3(6):e2386. doi: 10.1371/journal.pone.0002386.
Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders.
METHODOLOGY/PRINCIPAL FINDINGS: Here we describe the use of an HMM search of functional Pfam domains found in the key components of the ubiquitin-mediated pathway necessary to activate and reversibly modify target proteins in eight apicomplexan parasitic protozoa for which complete or late-stage genome projects exist. In parallel, the same search was conducted on five model organisms, single-celled and metazoans, to generate data to validate both the search parameters employed and aid paralog classification in Apicomplexa. For each of the 13 species investigated, a set of proteins predicted to be involved in the ubiquitylation pathway has been identified and demonstrates increasing component members of the ubiquitylation pathway correlating with organism and genome complexity. Sequence homology and domain architecture analyses facilitated prediction of apicomplexan-specific protein function, particularly those involved in regulating cell division during these parasite's complex life cycles.
CONCLUSIONS/SIGNIFICANCE: This study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathway in a wide variety of cellular processes, our data is a key step in elucidating the biological networks that, in part, direct the pathogenicity of these parasites resulting in a massive impact on global health. Moreover, apicomplexan-specific adaptations of the ubiquitylation pathway may represent new therapeutic targets for much needed drugs against apicomplexan parasites.
通过连接泛素或类泛素修饰剂对蛋白质进行可逆修饰是真核生物中一种重要的翻译后调控机制。泛素或类泛素蛋白的缀合已被证明在所有真核生物的生长、适应和稳态中发挥作用，泛素介导系统的紊乱与许多人类疾病的发病机制相关，包括癌症和神经退行性疾病。
方法/主要发现：在此，我们描述了使用隐马尔可夫模型（HMM）搜索在泛素介导途径的关键组分中发现的功能性Pfam结构域，这些关键组分是激活和可逆修饰八种顶复门寄生原生动物中靶蛋白所必需的，目前已有这些原生动物的完整或晚期基因组计划。同时，对五种模式生物（单细胞生物和后生动物）进行了相同的搜索，以生成数据来验证所采用的搜索参数，并辅助顶复门生物中的旁系同源物分类。对于所研究的13个物种中的每一个，已经鉴定出一组预测参与泛素化途径的蛋白质，并表明泛素化途径的组分成员增加与生物体和基因组复杂性相关。序列同源性和结构域结构分析有助于预测顶复门生物特异性蛋白质的功能，特别是那些在这些寄生虫复杂生命周期中参与调节细胞分裂的蛋白质。
结论/意义：本研究对预测参与顶复门生物泛素介导途径的蛋白质进行了全面分析。鉴于该途径在多种细胞过程中的重要性，我们的数据是阐明部分指导这些寄生虫致病性从而对全球健康产生巨大影响的生物网络的关键一步。此外，泛素化途径的顶复门生物特异性适应性可能代表针对顶复门寄生虫急需药物的新治疗靶点。
