Structure of NFAT Bound to DNA as a Monomer
Abstract
The nuclear factor of activated T cells (NFAT) is a calcium-dependent transcription factor that cooperates with a myriad of partner transcription factors to regulate distinct transcription programs. Transcription activation by NFAT without the cooperation of co-stimulatory signals in lymphocytes can also impose a genetic program of anergy. Although the ternary NFAT1/Fos-Jun/DNA complex has been structurally characterized, how NFAT1 recognizes DNA in the absence of cooperative partners and how such a binary NFAT/DNA complex may lead to the assembly of distinct high-order NFAT transcription complexes are still poorly understood. We have determined the crystal structure of the entire Rel homology region (RHR) of human NFAT1 (NFATc2) bound to DNA as a monomer. We also present footprinting evidence that corroborates the protein-DNA contacts observed in the crystal structure. Our structural and biochemical studies reveal the mechanism by which the monomeric Rel protein NFAT recognizes its cognate DNA site. A remarkable feature of the binary NFAT/DNA complex is the conformational flexibility exhibited by NFAT1 in the four independent copies of the NFAT/DNA complex in the crystal structure, which may reflect a mechanism by which NFAT1 interacts with a variety of protein partners as it mediates disparate biological responses.
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Structural analysis places NFATc2 T483 in the REL-homology region, T483 and T733 close to the DNA binding surface, and T862, T870, and T893 in the flexible C-terminal region associated with NFATc2 translocation.
“Analysis of publicly available crystal structures of NFATc2 revealed that T483 is located in the REL-homology region (aa 408–677), T483 and T733 are located close to the DNA binding surface (PDB: 1P7H and 1OWR) (40), and the remaining three threonine (T862, T870, and T893) are present in the flexible C-terminal region (aa 678–925) associated with NFATc2 translocation (Fig. 6A) (41).”
From LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies (2020) · cites this paper as [41]
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Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA
Chen, L., Glover, J. N. M., Hogan, P. G., Rao, A., & Harrison, S. C. (1998) · Nature · doi:10.1038/32100 · Cited by 521 · see citing works
Self-citationOnly one of the two DNA-bound orientations of AP-1 found in solution cooperates with NFATp
Chen, L., Oakley, M. G., Mark Glover, J. N., Jain, J., B. Dervan, P., Hogan, P. G., Rao, A., & Verdine, G. L. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00178-3 · Cited by 64 · see citing works
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Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance
Soto-Nieves, N., Puga, I., Abe, B. T., Bandyopadhyay, S., Baine, I., Rao, A., & Macian, F. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20082731 · Cited by 86 · see citing works
LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies
Kim, C., Beilina, A., Smith, N., Li, Y., Kim, M., Kumaran, R., Kaganovich, A., Mamais, A., Adame, A., Iba, M., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay0399 · Cited by 79 · see citing works
- Authors
- Stroud, J. C., & Chen, L.
- Affiliations
- University of Colorado Boulder (US)
- Corresponding author
- Chen, Lin
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 334
- Issue
- 5
- Pages
- 1009-1022
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2067011369
- Cited by
- 35
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 3 · 2016: 2 · 2012: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- Damon Runyon Cancer Research Foundation
- National Institute of General Medical Sciences (R01GM064642)
- National Institute of Allergy and Infectious Diseases (R21AI049905)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- NFAT1, NFATc2, protein-DNA complex, DNA binding, conformational flexibility, protein-DNA contacts, crystal structure, footprinting
- MeSH terms
- Amino Acid Sequence, Base Sequence, DNA, DNA-Binding Proteins, Humans, Models, Molecular, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Protein Conformation, Transcription Factors, Sequence Homology, Amino Acid, DNA Primers, Crystallography, X-Ray, DNA Footprinting, Electrophoretic Mobility Shift Assay, NFATC Transcription Factors
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