Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing
Year of publication
2017
Authors
Seppälä, Jonne; Bernardi, Rafael C.; Haataja, Tatu; Hellman, Maarit; Pentikäinen, Olli; Schulten, Klaus; Permi, Perttu; Ylänne, Jari; Pentikäinen, Ulla
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.
Show moreOrganizations and authors
University of Jyväskylä
Seppälä Jonne
Publication type
Publication format
Article
Parent publication type
Journal
Article type
Original article
Audience
ScientificPeer-reviewed
Peer-ReviewedMINEDU's publication type classification code
A1 Journal article (refereed), original researchPublication channel information
Journal
Publisher
Volume
7
Article number
4218
ISSN
Publication forum
Publication forum level
2
Open access
Open access in the publisher’s service
Yes
Open access of publication channel
Fully open publication channel
Self-archived
Yes
Other information
Fields of science
Biochemistry, cell and molecular biology
Keywords
[object Object],[object Object]
Publication country
United Kingdom
Internationality of the publisher
International
Language
English
International co-publication
Yes
Co-publication with a company
No
DOI
10.1038/s41598-017-04441-x
The publication is included in the Ministry of Education and Culture’s Publication data collection
Yes