Jonne Seppälä, Rafael C. Bernardi, Tatu J. K. Haataja, Maarit Hellman,
Olli T. Pentikäinen, Klaus Schulten, Perttu Permi, Jari Ylänne, and
Ulla Pentikäinen.
Skeletal dysplasia mutations effect on human filamins' structure and
mechanosensing.
Scientific Reports, 7:4218, 2017.
(PMC: PMC5484675)
SEPP2017
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.
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