先天性白内障相关HSF4 dna结合区错义突变的结构分析

IF 3.5 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zaiyu Xiao , Ling Guo , Yang Zhang , Liwei Cui , Yujie Dai , Zhu Lan , Qinghua Zhang , Sheng Wang , Wei Liu
{"title":"先天性白内障相关HSF4 dna结合区错义突变的结构分析","authors":"Zaiyu Xiao ,&nbsp;Ling Guo ,&nbsp;Yang Zhang ,&nbsp;Liwei Cui ,&nbsp;Yujie Dai ,&nbsp;Zhu Lan ,&nbsp;Qinghua Zhang ,&nbsp;Sheng Wang ,&nbsp;Wei Liu","doi":"10.1016/j.yjsbx.2019.100015","DOIUrl":null,"url":null,"abstract":"<div><p>Congenital cataract (CC) is the major cause of childish blindness, and nearly 50% of CCs are hereditary disorders. HSF4, a member of the heat shock transcription factor family, acts as a key regulator of cell growth and differentiation during the development of sensory organs. Missense mutations in the HSF4-encoding gene have been reported to cause CC formation; in particular, those occurring within the DNA-binding domain (DBD) are usually autosomal dominant mutations. To address how the identified mutations lead to HSF4 malfunction by placing adverse impacts on protein structure and DNA-binding specificity and affinity, we determined two high-resolution structures of the wild-type DBD and the K23N mutant of human HSF4, built DNA-binding models, conducted <em>in silico</em> mutations and molecular dynamics simulations. Our analysis suggests four possible structural mechanisms underlining the missense mutations in HSF4-DBD and cataractogenesis: (i), disruption of HSE recognition; (ii), perturbation of protein-DNA interactions; (iii), alteration of protein folding; (iv), other impacts, e.g. inhibition of protein oligomerization.</p></div>","PeriodicalId":17238,"journal":{"name":"Journal of Structural Biology: X","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.yjsbx.2019.100015","citationCount":"5","resultStr":"{\"title\":\"Structural analysis of missense mutations occurring in the DNA-binding domain of HSF4 associated with congenital cataracts\",\"authors\":\"Zaiyu Xiao ,&nbsp;Ling Guo ,&nbsp;Yang Zhang ,&nbsp;Liwei Cui ,&nbsp;Yujie Dai ,&nbsp;Zhu Lan ,&nbsp;Qinghua Zhang ,&nbsp;Sheng Wang ,&nbsp;Wei Liu\",\"doi\":\"10.1016/j.yjsbx.2019.100015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Congenital cataract (CC) is the major cause of childish blindness, and nearly 50% of CCs are hereditary disorders. HSF4, a member of the heat shock transcription factor family, acts as a key regulator of cell growth and differentiation during the development of sensory organs. Missense mutations in the HSF4-encoding gene have been reported to cause CC formation; in particular, those occurring within the DNA-binding domain (DBD) are usually autosomal dominant mutations. To address how the identified mutations lead to HSF4 malfunction by placing adverse impacts on protein structure and DNA-binding specificity and affinity, we determined two high-resolution structures of the wild-type DBD and the K23N mutant of human HSF4, built DNA-binding models, conducted <em>in silico</em> mutations and molecular dynamics simulations. Our analysis suggests four possible structural mechanisms underlining the missense mutations in HSF4-DBD and cataractogenesis: (i), disruption of HSE recognition; (ii), perturbation of protein-DNA interactions; (iii), alteration of protein folding; (iv), other impacts, e.g. inhibition of protein oligomerization.</p></div>\",\"PeriodicalId\":17238,\"journal\":{\"name\":\"Journal of Structural Biology: X\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2020-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/j.yjsbx.2019.100015\",\"citationCount\":\"5\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Structural Biology: X\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590152419300133\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Structural Biology: X","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590152419300133","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 5

摘要

先天性白内障(CC)是儿童失明的主要原因,近50%的CC是遗传性疾病。HSF4是热休克转录因子家族的一员,在感觉器官发育过程中对细胞生长和分化起着关键的调节作用。据报道,hsf4编码基因的错义突变可导致CC的形成;特别是发生在dna结合域(DBD)内的突变通常是常染色体显性突变。为了研究已鉴定的突变如何通过对蛋白质结构和dna结合特异性和亲和力的不利影响而导致HSF4功能障碍,我们确定了野生型DBD和人类HSF4 K23N突变体的两种高分辨率结构,建立了dna结合模型,进行了硅突变和分子动力学模拟。我们的分析提出了HSF4-DBD错义突变和白内障发生的四种可能的结构机制:(i)破坏HSE识别;(ii)蛋白质- dna相互作用的扰动;(iii)蛋白质折叠的改变;(iv)其他影响,例如抑制蛋白质寡聚化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural analysis of missense mutations occurring in the DNA-binding domain of HSF4 associated with congenital cataracts

Structural analysis of missense mutations occurring in the DNA-binding domain of HSF4 associated with congenital cataracts

Congenital cataract (CC) is the major cause of childish blindness, and nearly 50% of CCs are hereditary disorders. HSF4, a member of the heat shock transcription factor family, acts as a key regulator of cell growth and differentiation during the development of sensory organs. Missense mutations in the HSF4-encoding gene have been reported to cause CC formation; in particular, those occurring within the DNA-binding domain (DBD) are usually autosomal dominant mutations. To address how the identified mutations lead to HSF4 malfunction by placing adverse impacts on protein structure and DNA-binding specificity and affinity, we determined two high-resolution structures of the wild-type DBD and the K23N mutant of human HSF4, built DNA-binding models, conducted in silico mutations and molecular dynamics simulations. Our analysis suggests four possible structural mechanisms underlining the missense mutations in HSF4-DBD and cataractogenesis: (i), disruption of HSE recognition; (ii), perturbation of protein-DNA interactions; (iii), alteration of protein folding; (iv), other impacts, e.g. inhibition of protein oligomerization.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Structural Biology: X
Journal of Structural Biology: X Biochemistry, Genetics and Molecular Biology-Structural Biology
CiteScore
6.50
自引率
0.00%
发文量
20
审稿时长
62 days
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信