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Title: Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing

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.

Authors:
 [1];  [2];  [1];  [3];  [1];  [4];  [5];  [1];  [1]
  1. Univ. of Jyvaskyla (Finland). Dept. of Biological and Environmental Science. Nanoscience Center
  2. Univ. of Illinois, Champaign, IL (United States). Beckman Inst. for Advanced Science and Technology
  3. Univ. of Jyvaskyla (Finland). Dept. of Chemistry
  4. Univ. of Illinois, Champaign, IL (United States). Beckman Inst. for Advanced Science and Technology. Dept. of Physics
  5. Univ. of Jyvaskyla (Finland). Dept. of Biological and Environmental Science. Nanoscience Center. Dept. of Chemistry
Publication Date:
Research Org.:
Univ. of Illinois at Urbana-Champaign, IL (United States); Univ. of Jyvaskyla (Finland)
Sponsoring Org.:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Academy of Finland
OSTI Identifier:
1490409
Grant/Contract Number:  
AC02-05CH11231; 9P41GM104601; 283481; 138327; 278668; 288235; 2000268; jyy2516
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; computational biophysics; cytoskeletal proteins; NMR spectroscopy; SAXS; X-ray crystallography

Citation Formats

Seppälä, Jonne, Bernardi, Rafael C., Haataja, Tatu J. K., Hellman, Maarit, Pentikäinen, Olli T., Schulten, Klaus, Permi, Perttu, Ylänne, Jari, and Pentikäinen, Ulla. Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing. United States: N. p., 2017. Web. doi:10.1038/s41598-017-04441-x.
Seppälä, Jonne, Bernardi, Rafael C., Haataja, Tatu J. K., Hellman, Maarit, Pentikäinen, Olli T., Schulten, Klaus, Permi, Perttu, Ylänne, Jari, & Pentikäinen, Ulla. Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing. United States. doi:10.1038/s41598-017-04441-x.
Seppälä, Jonne, Bernardi, Rafael C., Haataja, Tatu J. K., Hellman, Maarit, Pentikäinen, Olli T., Schulten, Klaus, Permi, Perttu, Ylänne, Jari, and Pentikäinen, Ulla. Mon . "Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing". United States. doi:10.1038/s41598-017-04441-x. https://www.osti.gov/servlets/purl/1490409.
@article{osti_1490409,
title = {Skeletal Dysplasia Mutations Effect on Human Filamins’ Structure and Mechanosensing},
author = {Seppälä, Jonne and Bernardi, Rafael C. and Haataja, Tatu J. K. and Hellman, Maarit and Pentikäinen, Olli T. and Schulten, Klaus and Permi, Perttu and Ylänne, Jari and Pentikäinen, Ulla},
abstractNote = {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.},
doi = {10.1038/s41598-017-04441-x},
journal = {Scientific Reports},
issn = {2045-2322},
number = ,
volume = 7,
place = {United States},
year = {2017},
month = {6}
}

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Figures / Tables:

Figure 1 Figure 1: Schematic representation of Filamin. (a) Schematic representation of FLN dimer having 24 Ig-domains (blue) and the actin-binding domain (ABD, orange) in monomer. The two monomers are dimerized via domains 24. The atomic detailed structures of Ig-domains that form compact structures by interacting with the neighboring domains are highlightedmore » and shown in green, and the domains 16 and 17 studied here are shown in light red and light blue, respectively. The structures of compact domain fragments are shown in panel (b) (FLNa16-21) and in panel (c) (FLNa3-5). The FLNa16-21 model shown in (b) is obtained from SAXS using the high resolution structures of FLNa16-17, FLNa18-19, and FLNa20-21. (d) Shows the structure of the domain pair FLNa16-17 studied here. The binding mode of GPIbα-peptide (orange) to groove between the strands C and D of FLNa17 is shown. The FLNa16-17 - GPIbα-peptide structure is obtained by superimposing FLNa17-GPIbα-peptide X-ray structure with FLNa16-17 structure. L1788, whose mutation to arginine causes FMD is shown as ticks.« less

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    Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.