Molecular Basis of Filamin A-FilGAP Interaction and Its Impairment in Congenital Disorders Associated with Filamin A Mutations
Nakamura, F., Heikkinen, O., Pentikäinen, O., Osborn, T., Kasza, K., Weitz, D., Kupiainen, O., Permi, P., Kilpeläinen, I., Ylänne, J., Hartwig, J., & Stossel, T. (2009). Molecular Basis of Filamin A-FilGAP Interaction and Its Impairment in Congenital Disorders Associated with Filamin A Mutations. PloS One, 4(3), e4928. https://doi.org/10.1371/journal.pone.0004928
Julkaistu sarjassa
PloS OneTekijät
Päivämäärä
2009Tekijänoikeudet
© 2009 Nakamura et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License.
Background: Mutations in filamin A (FLNa), an essential cytoskeletal protein with multiple binding partners, cause
developmental anomalies in humans.
Methodology/Principal Findings: We determined the structure of the 23rd Ig repeat of FLNa (IgFLNa23) that interacts with
FilGAP, a Rac-specific GTPase-activating protein and regulator of cell polarity and movement, and the effect of the three
disease-related mutations on this interaction. A combination of NMR structural analysis and in silico modeling revealed the
structural interface details between the C and D b-strands of the IgFLNa23 and the C-terminal 32 residues of FilGAP.
Mutagenesis of the predicted key interface residues confirmed the binding constraints between the two proteins. Specific
loss-of-function FLNa constructs were generated and used to analyze the importance of the FLNa-FilGAP interaction in vivo.
Point mutagenesis revealed that disruption of the FLNa-FilGAP interface perturbs cell spreading. FilGAP does not bind FLNa
homologs FLNb or FLNc establishing the importance of this interaction to the human FLNa mutations. Tight complex
formation requires dimerization of both partners and the correct alignment of the binding surfaces, which is promoted by a
flexible hinge domain between repeats 23 and 24 of FLNa. FLNa mutations associated with human developmental
anomalies disrupt the binding interaction and weaken the elasticity of FLNa/F-actin network under high mechanical stress.
Conclusions/Significance: Mutational analysis informed by structure can generate reagents for probing specific cellular
interactions of FLNa. Disease-related FLNa mutations have demonstrable effects on FLNa function.
...
Julkaisija
Public Library of ScienceISSN Hae Julkaisufoorumista
1932-6203
Alkuperäislähde
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004928Julkaisu tutkimustietojärjestelmässä
https://converis.jyu.fi/converis/portal/detail/Publication/18688973
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