Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis.
Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis.
复制标题
DOI：
10.1038/s41467-021-23691-y
复制
发表时间：
2021-06-07
影响因子：
16.6
通讯作者：
Zweckstetter M
中科院分区：
文献类型：
--
作者：
Babu M;Favretto F;de Opakua AI;Rankovic M;Becker S;Zweckstetter M
肌萎缩侧索硬化症和额颞叶痴呆是两种临床特征重叠的神经退行性疾病，其病理标志是错误折叠蛋白质的细胞质沉积。这些疾病的家族性形式的最常见原因是C9 ORF 72基因的非编码区中的六核苷酸重复扩增，其被翻译成二肽重复聚合物。在这里，我们表明，脯氨酸/精氨酸重复聚合物脱轨蛋白质折叠螯合分子伴侣。我们证明，脯氨酸/精氨酸重复聚合物抑制PPIA的折叠催化剂活性，PPIA是一种丰富的分子伴侣和脯氨酰异构酶，在肌萎缩侧索硬化症的大脑中被改变。NMR光谱表明，脯氨酸/精氨酸重复聚合物结合到PPIA的活性位点。X射线晶体学确定了脯氨酸/精氨酸重复聚合物与脯氨酰异构酶复合的原子结构，并确定了疾病相关脯氨酸/精氨酸聚合物相互作用特异性的分子基础。综合数据建立了一种毒性机制，该机制对脯氨酸/精氨酸二肽重复聚合物具有特异性，并导致C9 orf 72相关神经退行性疾病中的蛋白质稳态脱轨。家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的最常见原因是C9 ORF 72基因非编码区的六核苷酸重复扩增，其被翻译成五种二肽重复（DPR）蛋白。在这里，作者表明，脯氨酸/精氨酸（PR）DPR抑制脯氨酰异构酶PPIA，并通过进行NMR测量和确定PR DPR结合PPIA晶体结构揭示PPIA蛋白质折叠活性受损的分子机制。
Amyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases. The most frequent cause of familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are hexanucleotide repeat expansions in the non-coding region of the C9ORF72 gene that are translated into five dipeptide repeat (DPR) proteins. Here, the authors show that proline/arginine (PR) DPRs inhibit the prolyl isomerase PPIA and reveal the molecular mechanism of the impaired protein folding activity of PPIA by performing NMR measurements and determining a PR DPR bound PPIA crystal structure.
登录
查看更多内容
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1126/science.1254917
发表时间：
2014-09-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
通讯作者：
McKnight SL
影响因子：
11.2
作者：
Ciura, Sorana;Lattante, Serena;Kabashi, Edor
通讯作者：
Kabashi, Edor
影响因子：
2.8
作者：
BODENHAUSEN, G;RUBEN, DJ
通讯作者：
RUBEN, DJ
影响因子：
56.9
作者：
Eisenmesser, EZ;Bosco, DA;Kern, D
通讯作者：
Kern, D