Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding: prediction and rational design.
Open accessAbstract
We propose an interhelical salt bridge rule to explain the dimerization specificity between the two amphipathic alpha-helices in the leucine zipper structure. Using the bZIP class of DNA-binding proteins as a model system, we predicted and designed novel dimerization partners. We predicted that ATF4, a member of the ATF/CREB family of transcription factors, would preferentially form heterodimers with IGEBP1, a member of the C/EBP superfamily. These predictions were verified using a gel mobility-shift assay. To further test the value of this interhelical salt bridge rule, we modified the bZIP protein C/EBP attempting to design molecules that would form preferentially heterodimers with C/EBP or molecules that would not interact with C/EBP. These designed molecules behaved as predicted. Therefore, we conclude that this interhelical salt bridge rule is useful in understanding the dimerization specificity of bZIP proteins. In addition, we suggest that this rule could be used to design novel "dominant-negative" molecules to specifically inhibit the function of target leucine zipper proteins in vivo.
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Altering the amino acids at the e and g positions can be enough to change a leucine zipper's dimerization specificity.
“Changing the amino acids at the e and g positions can be sufficient to change the dimerization specificity of a leucine zipper (Schuermann et al., 1991; O'Shea et al., 1992, 1993; Vinson et al., 1993; John et al., 1994; Zhou et al., 1994a, 1994b).”
From Oligomerization properties of GCN4 leucine zipper <i>e</i> and <i>g</i> position mutants (1997) · cites this paper as Vinson et al., 1993
The charge complementarity hypothesis predicts which leucine zipper pairs should or should not form heterodimers based on the net change in g-e' ion pairs between homodimers and heterodimers.
“The charge complementarity hypothesis (Vinson et al., 1993) predicts which pairs of leucine zippers should or should not form heterodimers based on the net increase or decrease in g-e' ion pairs formed in homodimers and heterodimers.”
From Oligomerization properties of GCN4 leucine zipper <i>e</i> and <i>g</i> position mutants (1997) · cites this paper as Vinson et al., 1993
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References 44 · Cited by 336
Research works printed but not linked: 3
- Hai, T. and T. Curran. 1991. Cross-family dimerization of tran- scription factors Fos/Jun and ATF/CREB alters DNA bind- ing specificity. Proc. Natl. Acad. Sci. 88" 3720-3724.
- Marqusee, S. and R. Baldwin. 1987. Helix stabilization by Glu... Lys salt bridges in short peptides of de novo design. Proc. Natl. Acad. Sci. 84: 8898-8902.
- Sanger, F., S. Nicklen, and A. Coulson. 1977. DNA sequencing with chain-terminating inhibitors. Proc. Natl. Acad. Sci. 74: 5463-5467.
- Authors
- Vinson, C. R., Hai, T., & Boyd, S. M.
- Affiliations
- National Institutes of Health (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1993-06
- Volume
- 7
- Issue
- 6
- Pages
- 1047-1058
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2054421559
- Cited by
- 336
- References
- 44
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 10 · 2020: 4 · 2019: 11 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 9 · 2014: 6 · 2013: 3 · 2012: 8
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- bZIP transcription factors, leucine zipper, amphipathic helix, ATF4, C/EBP, heterodimerization, protein design, dominant negative inhibitor, DNA binding
- MeSH terms
- Amino Acid Sequence, Animals, Blood Proteins, DNA, DNA-Binding Proteins, Lymphokines, Mammals, Molecular Sequence Data, Mutation, Plant Proteins, Transcription Factors, Leucine Zippers, Cyclic AMP Response Element-Binding Protein, Prostatic Secretory Proteins, Basic-Leucine Zipper Transcription Factors, Activating Transcription Factors, Activating Transcription Factor 4, G-Box Binding Factors
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