Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF
Open accessAbstract
Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte development and an important oncogene in melanoma. MITF heterodimeric assembly with related basic helix–loop–helix leucine zipper transcription factors is highly restricted, and its binding profile to cognate DNA sequences is distinct. Here, we determined the crystal structure of MITF in its apo conformation and in the presence of two related DNA response elements, the E-box and M-box. In addition, we investigated mouse and human Mitf mutations to dissect the functional significance of structural features. Owing to an unusual three-residue shift in the leucine zipper register, the MITF homodimer shows a marked kink in one of the two zipper helices to allow an out-of-register assembly. Removal of this insertion relieves restricted heterodimerization by MITF and permits assembly with the transcription factor MAX. Binding of MITF to the M-box motif is mediated by an unusual nonpolar interaction by Ile212, a residue that is mutated in mice and humans with Waardenburg syndrome. As several related transcription factors have low affinity for the M-box sequence, our analysis unravels how these proteins discriminate between similar target sequences. Our data provide a rational basis for targeting MITF in the treatment of important hereditary diseases and cancer.
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The tfecba6 allele is a recessive loss-of-function allele generated by CRISPR/Cas9, with a 6-nucleotide deletion in exon 7 predicted to interrupt critical spacing in the second alpha-helix of the dimerization domain.
“The tfecba6 allele shows recessive loss of function, and was generated via CRISPR/Cas9 directed mutagenesis. It corresponds to the deletion of 6 nucleotides from the 7th exon of the gene. This deletion of two amino acids is predicted to interrupt critical spacing in the second alpha-helix of the dimerization domain [35].”
From A systems biology approach uncovers the core gene regulatory network governing iridophore fate choice from the neural crest (2018) · cites this paper as [35]
The section ‘An unusual out-of-register leucine zipper restricts MITF assembly partners’ reports that a three-residue shift in MITF’s leucine zipper is crucial to its dimerization specificity. This supports the structural rationale for the cited prediction, but the paper does not examine the tfecba6 allele or predict the effect of its two-amino-acid deletion. It also does not establish the allele’s recessive loss of function, CRISPR/Cas9 origin, or exon 7 location. (LLM, conf=0.80)
Experimental — accuracy not yet measuredMitfa and Tfec have the potential to physically interact as a heterodimer.
“Notably, Mitfa and Tfec have the potential to physically interact as a heterodimer [57, 58], which adds an additional layer of complexity when attempting to elucidate the mechanism of cell fate choice.”
From The MITF paralog tfec is required in neural crest development for fate specification of the iridophore lineage from a multipotent pigment cell progenitor (2021) · cites this paper as [58]
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Cites
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Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming
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“crystallography for Mitf, which shares 86% sequence homology across the basic region with c-Myc (Figure S6C) (Pogenberg et al., 2012).”
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- Authors
- Pogenberg, V., Ögmundsdóttir, M. H., Bergsteinsdóttir, K., Schepsky, A., Phung, B., Deineko, V., Milewski, M., Steingrímsson, E., & Wilmanns, M.
- Affiliations
- European Molecular Biology Laboratory (DE)
- University of Iceland (IS)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-12-01
- Volume
- 26
- Issue
- 23
- Pages
- 2647-2658
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3521630
- OpenAlex
- W2127845119
- Cited by
- 137
- References
- 1
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 10 · 2020: 16 · 2019: 13 · 2018: 12 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 7 · 2013: 3
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron) (submittedVersion, other-oa)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- European Commission (LSHG-CT-2006-031220)
- European Synchrotron Radiation Facility
- Háskóli Íslands
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- MITF, microphthalmia-associated transcription factor, leucine zipper, transcription factor dimerization, DNA binding specificity, E-box, Max, bHLH transcription factors, crystal structure, Waardenburg syndrome, melanocyte development, melanoma, transcription factor mutations
- MeSH terms
- Amino Acid Sequence, Animals, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Waardenburg Syndrome, Leucine Zippers, Sequence Alignment, Protein Structure, Tertiary, Dimerization, Mice, Microphthalmia-Associated Transcription Factor
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