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dc.contributor.authorSeppälä, Jonne
dc.contributor.authorBernardi, Rafael C.
dc.contributor.authorHaataja, Tatu
dc.contributor.authorHellman, Maarit
dc.contributor.authorPentikäinen, Olli
dc.contributor.authorSchulten, Klaus
dc.contributor.authorPermi, Perttu
dc.contributor.authorYlänne, Jari
dc.contributor.authorPentikäinen, Ulla
dc.date.accessioned2017-07-04T09:26:37Z
dc.date.available2017-07-04T09:26:37Z
dc.date.issued2017
dc.identifier.citationSeppälä, 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. <i>Scientific Reports</i>, <i>7</i>, Article 4218. <a href="https://doi.org/10.1038/s41598-017-04441-x" target="_blank">https://doi.org/10.1038/s41598-017-04441-x</a>
dc.identifier.otherCONVID_27088940
dc.identifier.otherTUTKAID_74270
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/54830
dc.description.abstractCells’ 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.en
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofseriesScientific Reports
dc.relation.urihttps://www.nature.com/articles/s41598-017-04441-x.pdf
dc.subject.othercomputational biophysics
dc.subject.othercytoskeletal proteins
dc.subject.otherSAXS
dc.titleSkeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201706283098
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineSolu- ja molekyylibiologiafi
dc.contributor.oppiaineOrgaaninen kemiafi
dc.contributor.oppiaineNanoscience Centerfi
dc.contributor.oppiaineCell and Molecular Biologyen
dc.contributor.oppiaineOrganic Chemistryen
dc.contributor.oppiaineNanoscience Centeren
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2017-06-28T03:16:12Z
dc.type.coarjournal article
dc.description.reviewstatuspeerReviewed
dc.relation.issn2045-2322
dc.relation.numberinseries0
dc.relation.volume7
dc.type.versionpublishedVersion
dc.rights.copyright© the Authors, 2017. This is an open access article distributed under the terms of a Creative Commons License.
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber288235
dc.relation.grantnumber278668
dc.relation.grantnumber283481
dc.subject.ysoröntgenkristallografia
dc.subject.ysoNMR-spektroskopia
jyx.subject.urihttp://www.yso.fi/onto/yso/p29058
jyx.subject.urihttp://www.yso.fi/onto/yso/p26254
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.1038/s41598-017-04441-x
dc.relation.funderSuomen Akatemiafi
dc.relation.funderSuomen Akatemiafi
dc.relation.funderSuomen Akatemiafi
dc.relation.funderAcademy of Finlanden
dc.relation.funderAcademy of Finlanden
dc.relation.funderAcademy of Finlanden
jyx.fundingprogramAkatemiahanke, SAfi
jyx.fundingprogramAkatemiahanke, SAfi
jyx.fundingprogramAkatemiatutkijan tutkimuskulut, SAfi
jyx.fundingprogramAcademy Project, AoFen
jyx.fundingprogramAcademy Project, AoFen
jyx.fundingprogramResearch costs of Academy Research Fellow, AoFen
jyx.fundinginformationThis work was supported by Academy of Finland (283481 to UP, 138327 and 278668 to JY and 288235 to PP) and by the National Institutes of Health (NIH, 9P41GM104601 to KS). RCB is partially supported by the Energy Biosciences Institute (Regents of the University of California Berkeley - EBI 231 UCB BP 2014OO4J01 to KS). CSC-Finnish IT Center for Science is gratefully acknowledged for computational resources for steered molecular dynamics simulations (grants 2000268 and jyy2516 to UP). Dynamical network analysis of steered molecular dynamics simulations made use of the Texas Advanced Computing Center (TACC) as part of the Extreme Science Engineering Discovery Environment (XSEDE, MCA93S028 to K.S.) and NERSC/Edison supercomputer as part of the DoE ALCC program. Resources of the National Energy Research Scientific Computing Center (NERSC) are supported by Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231.


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© the Authors, 2017. This is an open access article distributed under the terms of a Creative Commons License.
Except where otherwise noted, this item's license is described as © the Authors, 2017. This is an open access article distributed under the terms of a Creative Commons License.