6EW1

Crystal structure of the Filamin A Ig-like domains 3-5 mutant P637Q

Summary for 6EW1

• Entry DOI: 10.2210/pdb6ew1/pdb
• Descriptor: Filamin-A (2 entities in total)
• Functional Keywords: actin binding protein, cell adhesion
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 31049.96

Authors

Haataja, T.J.K.,Pentikainen, U. (deposition date: 2017-11-03, release date: 2018-10-31, Last modification date: 2024-01-17)

Primary citation

Haataja, T.J.K.,Bernardi, R.C.,Lecointe, S.,Capoulade, R.,Merot, J.,Pentikainen, U.
Non-syndromic Mitral Valve Dysplasia Mutation Changes the Force Resilience and Interaction of Human Filamin A.
Structure, 27:102-112.e4, 2019

PubMed Abstract: 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 (FLNA-MVD). 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.

PubMed: 30344108
DOI: 10.1016/j.str.2018.09.007

Experimental method

X-RAY DIFFRACTION (2.3070081803 Å)