Tatu J.K. Haataja, Rafael C. Bernardi, Simon Lecointe, Romain Capoulade, Jean
Merot, and Ulla Pentikäinen.
Non-syndromic mitral valve dysplasia mutation changes the force
resilience and interaction of human Filamin A.
Structure, 27:102-112, 2019.
HAAT2019-RB
Filamin A (FLNa), expressed in endocardial endothelia during fetal valve
morphogenesis, is key in cardiac development. Missense mutations in FLNa
cause non-syndromic mitral valve dysplasia (FLNAMVD). Here, we aimed to
reveal the currently unknown underlying molecular mechanism behind FLNA-
MVD caused by the FLNa P637Q mutation. The solved crystal structure of
the
FLNa3-5 P637Q revealed that this mutation causes only minor structural
changes close to mutation site. These changes were observed to
significantly
affect FLNa’s ability to transmit cellular force and to interact with its binding
partner. The performed steered molecular dynamics simulations showed that
significantly lower forces are needed to split domains 4 and 5 in FLNA-MVD
than with wild-type FLNa. The P637Q mutation was also observed to
interfere
with FLNa’s interactions with the protein tyrosine phosphatase PTPN12. Our
results provide a crucial step toward understanding the molecular bases
behind
FLNA-MVD, which is critical for the development of drug-based
therapeutics.
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