Redefining the architecture of ferlin proteins: Insights into multi-domain protein structure and function.
Redefining the architecture of ferlin proteins: Insights into multi-domain protein structure and function.
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DOI：
10.1371/journal.pone.0270188
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
Ferlins是一种复杂的多结构域蛋白，参与膜运输、膜修复和胞吐作用。ferlin蛋白的大尺寸和对结构域边界缺乏共识已经减缓了理解ferlin蛋白结构和功能的分子水平细节的进展。然而，在硅蛋白折叠技术显著提高了我们对复杂的费林家族结构域结构的理解。我们使用RoseTTAFold对六种人ferlin蛋白（dysferlin, myoferlin, otoferlin, Fer1L4， Fer1L5和Fer1L6）的全长模型进行组装。我们的全长费林模型用于获得客观的领域边界，这些边界由AlphaFold2预测支持。尽管ferlin蛋白的氨基酸序列不同，但其结构域的范围和不同的子结构域是非常一致的。此外，RoseTTAFold/AlphaFold2的硅边界预测使我们能够描述和表征一个以前未知的C2结构域，在所有人类ferin中普遍存在，我们称之为C2- fera。目前，由全长度的硅模型所隐含的费林域-域相互作用预测精度较低；然而，使用RoseTTAFold和AlphaFold2作为域查找器已被证明是理解费林结构的强大研究工具。
Ferlins are complex, multi-domain proteins, involved in membrane trafficking, membrane repair, and exocytosis. The large size of ferlin proteins and the lack of consensus regarding domain boundaries have slowed progress in understanding molecular-level details of ferlin protein structure and function. However, in silico protein folding techniques have significantly enhanced our understanding of the complex ferlin family domain structure. We used RoseTTAFold to assemble full-length models for the six human ferlin proteins (dysferlin, myoferlin, otoferlin, Fer1L4, Fer1L5, and Fer1L6). Our full-length ferlin models were used to obtain objective domain boundaries, and these boundaries were supported by AlphaFold2 predictions. Despite the differences in amino acid sequence between the ferlin proteins, the domain ranges and distinct subdomains in the ferlin domains are remarkably consistent. Further, the RoseTTAFold/AlphaFold2 in silico boundary predictions allowed us to describe and characterize a previously unknown C2 domain, ubiquitous in all human ferlins, which we refer to as C2-FerA. At present, the ferlin domain-domain interactions implied by the full-length in silico models are predicted to have a low accuracy; however, the use of RoseTTAFold and AlphaFold2 as a domain finder has proven to be a powerful research tool for understanding ferlin structure.
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