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Crystal structure of progeria mutant S143F lamin A/C reveals increased hydrophobicity driving nuclear deformation

Lamins are intermediate filaments that form a 3-D meshwork in the periphery of the nuclear envelope. The recent crystal structure of a long fragment of human lamin A/C visualized the tetrameric assembly unit of the central rod domain as a polymerization intermediate. A genetic mutation of S143F caus...

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Detalles Bibliográficos
Autores principales: Ahn, Jinsook, Jeong, Soyeon, Kang, So-mi, Jo, Inseong, Park, Bum-Joon, Ha, Nam-Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956589/
https://www.ncbi.nlm.nih.gov/pubmed/35338226
http://dx.doi.org/10.1038/s42003-022-03212-3
Descripción
Sumario:Lamins are intermediate filaments that form a 3-D meshwork in the periphery of the nuclear envelope. The recent crystal structure of a long fragment of human lamin A/C visualized the tetrameric assembly unit of the central rod domain as a polymerization intermediate. A genetic mutation of S143F caused a phenotype characterized by both progeria and muscular dystrophy. In this study, we determined the crystal structure of the lamin A/C fragment harboring the S143F mutation. The obtained structure revealed the X-shaped interaction between the tetrameric units in the crystals, potentiated by the hydrophobic interactions of the mutated Phe143 residues. Subsequent studies indicated that the X-shaped interaction between the filaments plays a crucial role in disrupting the normal lamin meshwork. Our findings suggest the assembly mechanism of the 3-D meshwork and further provide a molecular framework for understanding the aging process by nuclear deformation.