首页> 外文期刊>Accounts of Chemical Research >Ligand Binding and Hydration in Protein Misfolding: Insights from Studies of Prion and p53 Tumor Suppressor Proteins
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Ligand Binding and Hydration in Protein Misfolding: Insights from Studies of Prion and p53 Tumor Suppressor Proteins

机译:配体结合和水合蛋白错误折叠:从Pri病毒和p53肿瘤抑制蛋白研究的见解。

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Protein misfolding has been implicated in a large number of diseases termed protein- folding disorders (PFDs), whichninclude Alzheimer’s disease, Parkinson’s disease, transmissible spongiform encephalopathies, familial amyloid poly-nneuropathy, Huntington’s disease, and type II diabetes. In these diseases, large quantities of incorrectly folded proteinsnundergo aggregation, destroying brain cells and other tissues.nThe interplay between ligand binding and hydration is an important component of the formation of misfolded protein spe-ncies. Hydration drives various biological processes, including protein folding, ligand binding, macromolecular assembly, enzymenkinetics, and signal transduction. The changes in hydration and packing, both when proteins fold correctly or when folding goesnwrong, leading to PFDs, are examined through several biochemical, biophysical, and structural approaches. Although in many casesnthe binding of a ligand such as a nucleic acid helps to prevent misfolding and aggregation, there are several examples in whichnligands induce misfolding and assembly into amyloids. This occurs simply because the formation of structured aggregates (suchnas protofibrillar and fibrillar amyloids) involves decreases in hydration, formation of a hydrogen-bond network in the secondarynstructure, and burying of nonpolar amino acid residues, processes that also occur in the normal folding landscape. In this Account,nwe describe the present knowledge of the folding and misfolding of different proteins, with a detailed emphasis on mammaliannprion protein (PrP) and tumoral suppressor protein p53; we also explore how ligand binding and hydration together influencenthe fate of the proteins.nAnfinsen’s paradigm that the structure of a protein is determined by its amino acid sequence is to some extent contradicted by thenobservation that there are two isoforms of the prion protein with the same sequence: the cellular and the misfolded isoform. The cellu-nlar isoform of PrP has a disordered N-terminal domain and a highly flexible, not-well-packed C-terminal domain, which might accountnfor its significant hydration. When PrP binds to biological molecules, such as glycosaminoglycans and nucleic acids, the disordered seg-nments appear to fold and become less hydrated. Formation of the PrP nucleic acid complex seems to accelerate the conversion ofnthe cellular form of the protein into the disease-causing isoform. For p53, binding to some ligands, including nucleic acids,nwould prevent misfolding of the protein. Recently, several groups have begun to analyze the folding misfolding of the indi-nvidual domains of p53, but several questions remain unanswered. We discuss the implications of these findings for under-nstanding the productive and incorrect folding pathways of these proteins in normal physiological states and in human disease,nsuch as prion disorders and cancer. These studies are shown to lay the groundwork for the development of new drugs.
机译:蛋白质折叠错误与许多被称为蛋白质折叠障碍(PFD)的疾病有关,其中包括阿尔茨海默氏病,帕金森氏病,可传播的海绵状脑病,家族性淀粉样多发性神经病,亨廷顿氏病和II型糖尿病。在这些疾病中,大量错误折叠的蛋白质会聚集,破坏脑细胞和其他组织。n配体结合与水合作用之间的相互作用是错误折叠蛋白质物种形成的重要组成部分。水合作用驱动各种生物过程,包括蛋白质折叠,配体结合,大分子组装,酶促反应和信号转导。通过几种生化,生物物理和结构方法研究了蛋白质正确折叠或折叠错误时导致PFD的水合作用和堆积变化。尽管在许多情况下,配体(例如核酸)的结合有助于防止错误折叠和聚集,但是有几个例子表明,配体诱导错误折叠和组装成淀粉状蛋白。发生这种情况的原因很简单,因为结构化聚集体(如原纤维和纤维状淀粉样蛋白)的形成涉及水合作用的减少,二级结构中氢键网络的形成以及非极性氨基酸残基的掩埋,这些过程也在正常的折叠环境中发生。在本报告中,我们描述了不同蛋白质折叠和错误折叠的当前知识,并特别强调了哺乳动物蛋白(PrP)和肿瘤抑制蛋白p53。我们还探讨了配体结合和水合如何影响蛋白质的命运。nAnfinsen的范式认为蛋白质的结构由其氨基酸序列决定,这在一定程度上与ob病毒蛋白质的两个同工型具有相同的序列相矛盾。 :细胞和错误折叠的亚型。 PrP的胞质亚型具有无序的N末端结构域和高度灵活的,堆积不充分的C末端结构域,这可能是其重要的水合作用的原因。当PrP结合至生物分子(例如糖胺聚糖和核酸)时,无序链段似乎会折叠并变得水合程度降低。 PrP核酸复合物的形成似乎加速了蛋白质的细胞形式向致病同工型的转化。对于p53,与某些配体(包括核酸)的结合将不会阻止蛋白质的错误折叠。最近,几个小组已经开始分析p53单个结构域的折叠错误折叠,但是仍有几个问题没有答案。我们讨论了这些发现对于理解正常生理状态和人类疾病(如病毒病和癌症)中这些蛋白质的生产性和错误折叠途径的意义。这些研究表明为新药的开发奠定了基础。

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