Fibril structures of TFG protein mutants validate the identification of TFG as a disease-related amyloid protein by the IMPAcT method.
Fibril structures of TFG protein mutants validate the identification of TFG as a disease-related amyloid protein by the IMPAcT method.
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DOI：
10.1093/pnasnexus/pgad402
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发表时间：
2023-12
期刊：
影响因子：
--
通讯作者：
Eisenberg, David S.
中科院分区：
文献类型：
--
作者：
Rosenberg, Gregory M.;Abskharon, Romany;Boyer, David R.;Ge, Peng;Sawaya, Michael R.;Eisenberg, David S.
关键词：
我们之前提出了一种生物信息学方法，用于识别由蛋白质低复杂结构域突变引起的疾病，该突变促使蛋白质进入致病淀粉样纤维。这样鉴定的一种蛋白质是原肌球蛋白受体激酶融合基因蛋白(TRK融合基因蛋白或TFG)。TFG基因突变与神经退行性疾病有关。在这里，我们提供的实验证据证实了我们的预测，即这些情况与淀粉样蛋白有关。我们发现TFG的低复杂性结构域包含与疾病相关的突变G269V或P285L，形成淀粉样纤维，并使用冷冻电子显微镜(Cryo-EM)确定其结构。这些结构在本质上无疑是淀粉样蛋白，并证实了突变的TFG低复杂性结构域形成淀粉样纤维的倾向。此外，尽管这些原纤维结构是由致病突变引起的，但它与其他被认为是非致病甚至具有功能的淀粉样结构有一些相似之处，但还有其他因素支持这些结构与疾病有关，包括与野生型序列相比形成淀粉样蛋白的倾向增加，突变残基本身对结构稳定的影响，以及双原丝状淀粉样蛋白核心。我们的发现阐明了一种先前未知的淀粉样蛋白的两种潜在的疾病相关结构，并表明致病淀粉样蛋白纤维的结构特征可能与通常与致病性相关的特征不一致。
We previously presented a bioinformatic method for identifying diseases that arise from a mutation in a protein's low-complexity domain that drives the protein into pathogenic amyloid fibrils. One protein so identified was the tropomyosin-receptor kinase–fused gene protein (TRK-fused gene protein or TFG). Mutations in TFG are associated with degenerative neurological conditions. Here, we present experimental evidence that confirms our prediction that these conditions are amyloid-related. We find that the low-complexity domain of TFG containing the disease-related mutations G269V or P285L forms amyloid fibrils, and we determine their structures using cryo-electron microscopy (cryo-EM). These structures are unmistakably amyloid in nature and confirm the propensity of the mutant TFG low-complexity domain to form amyloid fibrils. Also, despite resulting from a pathogenic mutation, the fibril structures bear some similarities to other amyloid structures that are thought to be nonpathogenic and even functional, but there are other factors that support these structures' relevance to disease, including an increased propensity to form amyloid compared with the wild-type sequence, structure-stabilizing influence from the mutant residues themselves, and double-protofilament amyloid cores. Our findings elucidate two potentially disease-relevant structures of a previously unknown amyloid and also show how the structural features of pathogenic amyloid fibrils may not conform to the features commonly associated with pathogenicity.
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影响因子：
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DOI：
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期刊：
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