University of Oulu

Kinnunen S, Välimäki M, Tölli M, Wohlfahrt G, Darwich R, Komati H, et al. (2015) Nuclear Receptor-Like Structure and Interaction of Congenital Heart Disease-Associated Factors GATA4 and NKX2-5. PLoS ONE 10(12): e0144145.

Nuclear receptor–like structure and interaction of congenital heart disease–associated factors GATA4 and NKX2–5

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Author: Kinnunen, Sini1,2; Välimäki, Mika1,2; Tölli, Marja2;
Organizations: 1Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland
2Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
3Orion Pharma, Computer-Aided Drug Design, Espoo, Finland
4Laboratory of Cardiac Development and Differentiation, Department of Biochemistry, Immunology and Microbiology, University of Ottawa, Ottawa, Canada
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.5 MB)
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Language: English
Published: Public Library of Science, 2015
Publish Date: 2020-05-14


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.

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Series: PLoS one
ISSN: 1932-6203
ISSN-E: 1932-6203
ISSN-L: 1932-6203
Volume: 10
Issue: 12
Article number: e0144145
DOI: 10.1371/journal.pone.0144145
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by grants from the Academy of Finland (266661) (HR), the Tekes large strategic research opening (project no. 40395/13) (HR), Sigrid Juselius Foundation (HR), the Finnish Foundation for Cardiovascular Research (HR) (the authors do not have specific grant numbers for these grants), and the Canadian Institute for Health Research (MN) (MOP36382). Funding for open access charge came from the Academy of Finland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Orion Pharma provided support in the form of salary for GW, but Orion Pharma or the funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of GW is articulated in the ‘author contributions’ section.
Academy of Finland Grant Number: 266661
Detailed Information: 266661 (Academy of Finland Funding decision)
Copyright information: © 2015 Kinnunen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.