5DCP

Crystal structure of the human filamin B Ig-like domains 16-17

Summary for 5DCP

• Entry DOI: 10.2210/pdb5dcp/pdb
• Descriptor: Filamin-B (2 entities in total)
• Functional Keywords: cytoskeleton, adhesion, immunoglobulin-like, actin binding protein, structural protein
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform 1: Cytoplasm, cell cortex. Isoform 2: Cytoplasm, cytoskeleton. Isoform 3: Cytoplasm, cytoskeleton. Isoform 6: Cytoplasm, cytoskeleton: O75369
• Total number of polymer chains: 2
• Total formula weight: 37498.29

Authors

Seppala, J.,Pentikainen, U.,Ylanne, J. (deposition date: 2015-08-24, release date: 2016-08-24, Last modification date: 2024-01-10)

Primary citation

Seppala, J.,Bernardi, R.C.,Haataja, T.J.K.,Hellman, M.,Pentikainen, O.T.,Schulten, K.,Permi, P.,Ylanne, J.,Pentikainen, U.
Skeletal Dysplasia Mutations Effect on Human Filamins' Structure and Mechanosensing.
Sci Rep, 7:4218-4218, 2017

PubMed 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.

PubMed: 28652603
DOI: 10.1038/s41598-017-04441-x

Experimental method

X-RAY DIFFRACTION (2.49 Å)