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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Vivian Pogenberg
  • Margret H. Ogmundsdottir
  • Kristin Bergsteinsdottir
  • Alexander Schepsky
  • Bengt Phung
  • Viktor Deineko
  • Morlin Milewski
  • Eirikur Steingrimsson
  • Matthias Wilmanns
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Genetics

Keywords

  • melanocyte regulation, transcription factor, DNA binding, leucine, zipper, crystal structure
Original languageEnglish
Pages (from-to)2647-2658
JournalGenes & Development
Volume26
Issue number23
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Experimental Clinical Chemistry (013016010)

Related research output

Bengt Phung, 2013, Experimental Clinical Chemistry. 93 p.

Research output: ThesisDoctoral Thesis (compilation)

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