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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...

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Detalles Bibliográficos
Autores principales: Xiao, Zaiyu, Guo, Ling, Zhang, Yang, Cui, Liwei, Dai, Yujie, Lan, Zhu, Zhang, Qinghua, Wang, Sheng, Liu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337047/
https://www.ncbi.nlm.nih.gov/pubmed/32647819
http://dx.doi.org/10.1016/j.yjsbx.2019.100015
Descripción
Sumario: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.