Critical Structural Defects Explain Filamin A Mutations Causing Mitral Valve Dysplasia

Mitral valve diseases affect approximately 3% of the population and are the most common reasons for valvular surgery because no drug-based treatments exist. Inheritable genetic mutations have now been established as the cause of mitral valve insufficiency, and four different missense mutations in the filamin A gene (FLNA) have been found in patients suffering from non-syndromic mitral valve dysplasia (MVD). The FLNA protein is expressed, in particular, in endocardial endothelia during fetal valve morphogenesis and is key in cardiac development. The FLNA-MVD causing mutations are clustered in the N-terminal region of FLNA. How the mutations in FLNA modify its structure and function, have mostly remained elusive. In this study, using NMR spectroscopy and interaction assays, we investigated FLNA-MVD causing V711D and H743P mutations. Our results clearly indicated that both mutations almost completely destroy the folding of the FLNA5 domain, where the mutation is located, and also affect the folding of the neighboring FLNA4 domain. The structure of the neighboring FLNA6 domain was not affected by the mutations. These mutations also completely abolish FLNA’s interactions with protein tyrosine phosphatase (PTP) non-receptor type 12 (PTPN12), which has been suggested to contribute to the pathogenesis of FLNA-MVD. Taken together, our results provide an essential structural and molecular framework for understanding the molecular bases of FLNA-MVD, which is crucial for the development of new therapies to replace surgery.peerReviewe

Quaternary structure of human, Drosophila melanogaster and Caenorhabditis elegans MFE-2 in solution from synchrotron small-angle X-ray scattering

Multifunctional enzyme type 2 (MFE-2) forms part of the fatty acid b-oxidation pathway in peroxisomes.MFE-2s from various species reveal proteins with structurally homologous functionaldomains assembled in different compilations. Crystal structures of all domain types are known.SAXS data from human, fruit fly and Caenorhabditis elegans MFE-2s and their constituent domainswere collected, and both ab initio and rigid body models constructed. Location of the putative substratebinding helper domain SCP-2L (sterol carrier protein 2-like), which is not part of MFE-2 proteinin every species and not seen as part of any previous MFE-2 structures, was determined. Theobtained models of human and C. elegans MFE-2 lend a direct structural support to the idea ofthe biological role of SCP-2L