A1 Journal article (refereed)
Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing (2017)
Seppälä, J., Bernardi, R. C., Haataja, T., Hellman, M., Pentikäinen, O., Schulten, K., Permi, P., Ylänne, J., & Pentikäinen, U. (2017). Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing. Scientific Reports, 7, Article 4218. https://doi.org/10.1038/s41598-017-04441-x
JYU authors or editors
Publication details
All authors or editors: Seppälä, Jonne; Bernardi, Rafael C.; Haataja, Tatu; Hellman, Maarit; Pentikäinen, Olli; Schulten, Klaus; Permi, Perttu; Ylänne, Jari; Pentikäinen, Ulla
Journal or series: Scientific Reports
ISSN: 2045-2322
eISSN: 2045-2322
Publication year: 2017
Volume: 7
Issue number: 0
Article number: 4218
Publisher: Nature Publishing Group
Publication country: United Kingdom
Publication language: English
DOI: https://doi.org/10.1038/s41598-017-04441-x
Persistent website address: https://www.nature.com/articles/s41598-017-04441-x.pdf
Publication open access: Openly available
Publication channel open access: Open Access channel
Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/54830
Abstract
Cells’ ability to sense mechanical cues in their environment is crucial for fundamental cellular processes, leading defects in mechanosensing to be linked to many diseases. The actin cross-linking protein Filamin has an important role in the conversion of mechanical forces into biochemical signals. Here, we reveal how mutations in Filamin genes known to cause Larsen syndrome and Frontometaphyseal dysplasia can affect the structure and therefore function of Filamin domains 16 and 17. Employing X-ray crystallography, the structure of these domains was first solved for the human Filamin B. The interaction seen between domains 16 and 17 is broken by shear force as revealed by steered molecular dynamics simulations. The effects of skeletal dysplasia associated mutations of the structure and mechanosensing properties of Filamin were studied by combining various experimental and theoretical techniques. The results showed that Larsen syndrome associated mutations destabilize or even unfold domain 17. Interestingly, those Filamin functions that are mediated via domain 17 interactions with other proteins are not necessarily affected as strongly interacting peptide binding to mutated domain 17 induces at least partial domain folding. Mutation associated to Frontometaphyseal dysplasia, in turn, transforms 16–17 fragment from compact to an elongated form destroying the force-regulated domain pair.
Keywords: NMR spectroscopy; x-ray crystallography
Free keywords: computational biophysics; cytoskeletal proteins; SAXS
Contributing organizations
Related projects
- Filamiinien fysiologisten ominaisuuksien
- Pentikäinen, Ulla
- Research Council of Finland
- Uudet filamiineista riippuvaiset mekanos
- Ylänne, Jari
- Research Council of Finland
- Conformational properties of intrinsically disordered proteins - biophysical characterization
- Permi, Perttu
- Research Council of Finland
Ministry reporting: Yes
Reporting Year: 2017
JUFO rating: 2