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 , Ling Guo , Yang Zhang , Liwei Cui , Yujie Dai , Zhu Lan , Qinghua Zhang , Sheng Wang , 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":"4 ","pages":"Article 100015"},"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 , Ling Guo , Yang Zhang , Liwei Cui , Yujie Dai , Zhu Lan , Qinghua Zhang , Sheng Wang , 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\":\"4 \",\"pages\":\"Article 100015\"},\"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}
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.