BACKGROUND Amyloidogenic proteins are most often associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, but there are more than two dozen human proteins known to form amyloid fibrils associated with disease. Lysozyme is an antimicrobial protein that is used as a general model to study amyloid fibril formation. Studies aimed at elucidating the process of amyloid formation of lysozyme tend to focus on partial unfolding of the native state due to the relative instability of mutant amyloidogenic variants. While this is well supported, the data presented here suggest the native structure of the variants may also play a role in primary nucleation. RESULTS Three-dimensional structural analysis identified lysozyme residues 21, 62, 104, and 122 as displaced in both amyloidogenic variants compared to wild type lysozyme. Residue interaction network (RIN) analysis found greater clustering of residues 112-117 in amyloidogenic variants of lysozyme compared to wild type. An analysis of the most energetically favored predicted dimers and trimers provided further evidence for a role for residues 21, 62, 104, 122, and 112-117 in amyloid formation. CONCLUSIONS This study used lysozyme as a model to demonstrate the utility of combining 3D structural analysis with RIN analysis for studying the general process of amyloidogenesis. Results indicated that binding of two or more amyloidogenic lysozyme mutants may be involved in amyloid nucleation by placing key residues (21, 62, 104, 122, and 112-117) in proximity before partial unfolding occurs. Identifying residues in the native state that may be involved in amyloid formation could provide novel drug targets to prevent a range of amyloidoses.

中文翻译：

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在计算机上预测涉及人I56T和D67H溶菌酶的淀粉样蛋白初级成核的新残基。

背景技术淀粉样蛋白生成蛋白最常与神经退行性疾病如阿尔茨海默氏病，帕金森氏病和亨廷顿氏病相关，但是已知有超过十二种人类蛋白形成与疾病相关的淀粉样蛋白原纤维。溶菌酶是一种抗菌蛋白，可用作研究淀粉样蛋白原纤维形成的通用模型。旨在阐明溶菌酶淀粉样蛋白形成过程的研究倾向于集中于天然状态的部分展开，这是由于突变的淀粉样蛋白生成变体相对不稳定。尽管对此有很好的支持，但此处提供的数据表明，变异体的天然结构也可能在初级成核中起作用。结果三维结构分析确定了溶菌酶残基21、62、104，与野生型溶菌酶相比，在两个淀粉样变种变体中有122个被置换。与野生型相比，残基相互作用网络（RIN）分析发现，在溶菌酶的淀粉样变体中，残基112-117的聚集性更大。对最受能量支持的预测的二聚体和三聚体的分析提供了进一步证据，证明了淀粉样蛋白形成中残基21、62、104、122和112-117的作用。结论本研究使用溶菌酶作为模型，证明将3D结构分析与RIN分析相结合用于研究淀粉样蛋白生成的一般过程的实用性。结果表明，通过在部分展开之前将关键残基（21、62、104、122和112-117）放置在附近，两个或多个淀粉样蛋白溶菌酶突变体的结合可能参与淀粉样蛋白的成核。