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

ABSTRACT: 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.

SUBMITTER: Ahn J 

PROVIDER: S-EPMC8956589 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature