Computational Modeling of the 3D Structure of Intermediate Filaments and Molecular Mechanism of Associated Diseases

Abstract

Intermediate filaments along with microtubules and microfilaments form the cytoskeletal structure in cells. Unlike the other two components, the molecular structure of the intermediate filament has not been determined at residue-level resolution. In this study, we determined the structure of the Keratin K5-K14 Intermediate filament using integrative modeling. Our model utilizes data from experiments such as chemical cross-linking, X-ray crystallography and SAXS to resolve the structure of large parts of the filamentous assembly. Our structure of the Keratin filament helps identify the molecular mechanisms behind hundreds of point mutants that disrupt the filament and hence lead to disease. Our model also suggests how filament bundles are formed and these findings are consistent with experimental observations that were not used in model construction. Further, we have been able to suggest and experimentally validate new mutations that lead to filament disruption. We believe that this first 3D model of the full-length intermediate filament would now help study other intermediate filaments. It would also be useful in designing therapeutic strategies against disease conditions that stem from filament instability.