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Structure-function analyses of a keratin heterotypic complex identify specific keratin regions involved in intermediate filament assembly

By Chang-Hun Lee, Min-Sung Kim, Shuang Li, Daniel J. Leahy, Pierre A. Coulombe

Posted 29 Oct 2019
bioRxiv DOI: 10.1101/821090 (published DOI: 10.1016/j.str.2020.01.002)

Intermediate filaments (IFs) provide vital mechanical support in a broad array of cell types. Interference with this role causes cell fragility and accounts for a large number of human diseases. Gaining an understanding IF structure is paramount to understanding their function and designing therapeutic agents for relevant diseases. Here, we report the 2.6 Angstroms resolution crystal structure of a complex of interacting 2B domains of keratin 5 (K5) and K14. K5 and K14 form a long-range, left-handle coiled coil, with participating alpha-helices aligned in parallel and in register. Follow-up mutagenesis revealed that specific contacts between interacting 2B domains play a crucial role during 10-nm IF assembly, likely at the step of octamer-octamer association. The resulting structural model represents the first atomic-resolution visualization of 2B-2B interactions consistent with the A22 dimer alignment and provide insight into the defects introduced by mutations in IF genes associated with human skin diseases.

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