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 Journal of Structural Biology: X Pub Date : 2020-01-01 DOI:10.1016/j.yjsbx.2019.100015
Zaiyu Xiao , Ling Guo , Yang Zhang , Liwei Cui , Yujie Dai , Zhu Lan , Qinghua Zhang , Sheng Wang , Wei Liu
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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。
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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.

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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
期刊最新文献
Corrigendum to “Minimizing ice contamination during specimen preparation for cryo-soft X-ray tomography and cryo-electron tomography” [J. Struct. Biol.: X 10(2024) 100113] Editorial by Natalie Reznikov [for Buss et al., “Hierarchical organization of bone in three dimensions: A twist of twists” (2022)] Structural analysis of the stable form of fibroblast growth factor 2 – FGF2-STAB Localization of albumin with correlative super resolution light- and electron microscopy in the kidney Minimizing ice contamination during specimen preparation for cryo-soft X-ray tomography and cryo-electron tomography
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