Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease-Associated Factors GATA4 and NKX2-5

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Kinnunen , S , Välimäki , M , Tölli , M , Wohlfahrt , G , Darwich , R , Komati , H , Nemer , M & Ruskoaho , H 2015 , ' Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease-Associated Factors GATA4 and NKX2-5 ' PLoS One , vol. 10 , no. 12 , 0144145 . DOI: 10.1371/journal.pone.0144145

Title: Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease-Associated Factors GATA4 and NKX2-5
Author: Kinnunen, Sini; Välimäki, Mika; Tölli, Marja; Wohlfahrt, Gerd; Darwich, Rami; Komati, Hiba; Nemer, Mona; Ruskoaho, Heikki
Contributor: University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
University of Helsinki, Division of Pharmacology and Pharmacotherapy
Date: 2015-12-07
Language: eng
Number of pages: 21
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/160567
Abstract: Aims Transcription factor GATA4 is a dosage sensitive regulator of heart development and alterations in its level or activity lead to congenital heart disease (CHD). GATA4 has also been implicated in cardiac regeneration and repair. GATA4 action involves combinatorial interaction with other cofactors such as NKX2-5, another critical cardiac regulator whose mutations also cause CHD. Despite its critical importance to the heart and its evolutionary conservation across species, the structural basis of the GATA4-NKX2-5 interaction remains incompletely understood. Methods and Results A homology model was constructed and used to identify surface amino acids important for the interaction of GATA4 and NKX2-5. These residues were subjected to site-directed mutagenesis, and the mutant proteins were characterized for their ability to bind DNA and to physically and functionally interact with NKX2-5. The studies identify 5 highly conserved amino acids in the second zinc finger (N272, R283, Q274, K299) and its C-terminal extension (R319) that are critical for physical and functional interaction with the third alpha helix of NKX2-5 homeodomain. Integration of the experimental data with computational modeling suggests that the structural arrangement of the zinc finger-homeodomain resembles the architecture of the conserved DNA binding domain of nuclear receptors. Conclusions The results provide novel insight into the structural basis for protein-protein interactions between two important classes of transcription factors. The model proposed will help to elucidate the molecular basis for disease causing mutations in GATA4 and NKX2-5 and may be relevant to other members of the GATA and NK classes of transcription factors.
Subject: TRANSCRIPTION FACTOR GATA-4
OF-FUNCTION MUTATION
DNA-BINDING TARGETS
CARDIAC TRANSCRIPTION
GENE-EXPRESSION
VENTRAL MORPHOGENESIS
MUTUAL COFACTORS
DEFINED FACTORS
TUBE FORMATION
ADULT HEART
317 Pharmacy
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