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Cited by 64Genomics and Chromatin DynamicsProtein Structure and DynamicsDiffusion and Search Dynamics

Only one of the two DNA-bound orientations of AP-1 found in solution cooperates with NFATp

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Chen, Lin, Oakley, Martha G., Mark Glover, J.N., Jain, Jugnu, B. Dervan, Peter, Hogan, Patrick G., Rao, Anjana, Verdine, Gregory L.·1995·Current Biology
DOI 10.1016/s0960-9822(95)00178-3
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Abstract

Background The transcription factor AP-1 activates the expression of numerous genes in response to mitogenic stimuli. AP-1 regulates gene expression both through solitary binding to independent recognition sites and, in cooperation with various heterologous transcription factors, through targeting to composite response elements. The two subunits that make up the AP-1 heterodimer, Fos and Jun, possess identical residues at positions that make sequence-specific contacts to DNA. This degeneracy leaves the protein with no apparent way of orienting itself uniquely on DNA by differentially recognizing its two non-identical half-sites. Here, we have analyzed the orientation of the AP-1 basic-leucine-zipper (bZip) domain on a cognate site, both alone and in the cooperative complex formed together with the 'nuclear factor of activated T cells' (NFATp).Results The results of affinity cleaving experiments demonstrate that, in solution, the AP-1 bZip binds DNA as a mixture of two orientational isomers. However, in the cooperative complex formed with NFATp on a composite response element, the AP-1 bZip adopts a single orientation, with Jun and Fos bound to the NFATp-proximal and NFATp-distal half-sites, respectively. Protein cross-linking experiments demonstrate that protein-protein contacts are responsible for this 'orientational locking'.Conclusions Our results demonstrate that, through protein-protein interactions, one protein can force another to adopt a single DNA-bound orientation. Thus, cooperative interactions between adjacent regulatory proteins can influence not only the energetics of their interactions with DNA, but also their precise geometric and stereochemical arrangement. Because orientational isomers present markedly different structures to the transcriptional apparatus, it seems likely that orientation will exert an effect on the ability to activate transcription.

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  • Cross-linking experiments showed NFAT-AP-1 adducts detectable only with specific DNA, arguing protein-protein interactions alone are insufficient.

    “cross-linking experiments have shown that NFAT-AP-1 adducts are detectable only in the presence of specific DNA, arguing that protein-protein interactions alone are of insufficient strength for productive complexation”

    From Assembly requirements of PU.1–Pip (IRF‐4) activator complexes: inhibiting function in vivo using fused dimers (1999) · cites this paper as Chen et al., 1995

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Authors
Chen, L., Oakley, M. G., Mark Glover, J. N., Jain, J., B. Dervan, P., Hogan, P. G., Rao, A., & Verdine, G. L.
Affiliations
  • Harvard University (US)
  • California Institute of Technology (US)
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
1995-08
Volume
5
Issue
8
Pages
882-889
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/s0960-9822(95)00178-3
OpenAlex
W2141215344
Cited by
64
References
40
Citations by year
2014: 1 · 2013: 1 · 2012: 2
FWCI
3.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
National Institute of General Medical Sciences (GM27681)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
Keywords
AP-1, FOS, c-Jun, protein-protein interaction, transcriptional activation, protein-DNA complex structure, protein cross-linking
MeSH terms
Amino Acid Sequence, Base Sequence, DNA, DNA-Binding Proteins, Molecular Sequence Data, Nuclear Proteins, Protein Binding, Protein Conformation, Transcription Factors, Transcription Factor AP-1, NFATC Transcription Factors

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