The N‐terminus of obscurin is flexible in solution
The N‐terminus of obscurin is flexible in solution
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暗色蛋白的 N 末端在溶液中具有灵活性
DOI：
10.1002/prot.26442
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Wright, Nathan T.
中科院分区：
文献类型：
--
作者：
Mauriello, Gianna E.;Moncure, Grace E.;Nowzari, Roujon A.;Miller, Callie J.;Wright, Nathan T.
巨型细胞骨架蛋白Oblcurin的N端一半由50多个Ig样结构域组成，串联排列。结构域18-51通过短的5-残基连接体彼此连接，并且这种排列先前已被证明在溶液中形成半柔性棒。结构域1-18通常具有略长的~7个残基的域间连接子，而这种连接子所提供的多域结构和运动尚未得到充分的研究。在这里，我们使用核磁共振、SAXS和MD来表明这些较长的连接子与显著更大的域/域灵活性相关，所产生的多域结构适度紧凑。进一步研究结构域间柔性和连接子长度之间的关系表明，存在5个残基的“甜蜜点”连接子长度，这导致双结构域系统被延伸，反之，较长或较短的连接子都导致较少延伸的结构。对Oblcurin N末端结构和灵活性的详细了解允许对结构域1-18进行数学建模，这表明如果单独在溶液中，该区域可能会形成缠结。考虑到蛋白质缠结在自然界中发生的频率是如此之低，并且考虑到当缠结确实出现时发生的病理结果，我们的数据表明暗黑蛋白很可能是显著地支架在细胞内或以其他方式在细胞内向外延伸。
The N‐terminal half of the giant cytoskeletal protein obscurin is comprised of more than 50 Ig‐like domains, arranged in tandem. Domains 18–51 are connected to each other through short 5‐residue linkers, and this arrangement has been previously shown to form a semi‐flexible rod in solution. Domains 1–18 generally have slightly longer ~7 residue interdomain linkers, and the multidomain structure and motion conferred by this kind of linker is understudied. Here, we use NMR, SAXS, and MD to show that these longer linkers are associated with significantly more domain/domain flexibility, with the resulting multidomain structure being moderately compact. Further examination of the relationship between interdomain flexibility and linker length shows there is a 5 residue “sweet spot” linker length that results in dual‐domain systems being extended, and conversely that both longer or shorter linkers result in a less extended structure. This detailed knowledge of the obscurin N terminus structure and flexibility allowed for mathematical modeling of domains 1–18, which suggests that this region likely forms tangles if left alone in solution. Given how infrequently protein tangles occur in nature, and given the pathological outcomes that occur when tangles do arise, our data suggest that obscurin is likely either significantly scaffolded or else externally extended in the cell.
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