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Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF

Pogenberg, Vivian; Ogmundsdottir, Margret H.; Bergsteinsdottir, Kristin; Schepsky, Alexander; Phung, Bengt LU ; Deineko, Viktor; Milewski, Morlin; Steingrimsson, Eirikur and Wilmanns, Matthias (2012) In Genes & Development 26(23). p.2647-2658
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
melanocyte regulation, transcription factor, DNA binding, leucine, zipper, crystal structure
in
Genes & Development
volume
26
issue
23
pages
2647 - 2658
publisher
Cold Spring Harbor Laboratory Press
external identifiers
  • wos:000311944000008
  • scopus:84870508533
ISSN
1549-5477
DOI
10.1101/gad.198192.112
language
English
LU publication?
yes
id
ac5f4882-81c4-4fa9-8776-4ab5584d56ab (old id 3372438)
date added to LUP
2013-02-01 06:59:30
date last changed
2017-10-29 04:05:36
@article{ac5f4882-81c4-4fa9-8776-4ab5584d56ab,
  abstract     = {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.},
  author       = {Pogenberg, Vivian and Ogmundsdottir, Margret H. and Bergsteinsdottir, Kristin and Schepsky, Alexander and Phung, Bengt and Deineko, Viktor and Milewski, Morlin and Steingrimsson, Eirikur and Wilmanns, Matthias},
  issn         = {1549-5477},
  keyword      = {melanocyte regulation,transcription factor,DNA binding,leucine,zipper,crystal structure},
  language     = {eng},
  number       = {23},
  pages        = {2647--2658},
  publisher    = {Cold Spring Harbor Laboratory Press},
  series       = {Genes & Development},
  title        = {Restricted leucine zipper dimerization and specificity of DNA recognition of the melanocyte master regulator MITF},
  url          = {http://dx.doi.org/10.1101/gad.198192.112},
  volume       = {26},
  year         = {2012},
}