Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif

Nucleic Acids Res. 2020 Jan 24;48(2):934-948. doi: 10.1093/nar/gkz1104.

Abstract

Interrupted dimeric coiled coil segments are found in a broad range of proteins and generally confer selective functional properties such as binding to specific ligands. However, there is only one documented case of a basic-helix-loop-helix leucine zipper transcription factor-microphthalmia-associated transcription factor (MITF)-in which an insertion of a three-residue stammer serves as a determinant of conditional partner selectivity. To unravel the molecular principles of this selectivity, we have analyzed the high-resolution structures of stammer-containing MITF and an engineered stammer-less MITF variant, which comprises an uninterrupted symmetric coiled coil. Despite this fundamental difference, both MITF structures reveal identical flanking in-phase coiled coil arrangements, gained by helical over-winding and local asymmetry in wild-type MITF across the stammer region. These conserved structural properties allow the maintenance of a proper functional readout in terms of nuclear localization and binding to specific DNA-response motifs regardless of the presence of the stammer. By contrast, MITF heterodimer formation with other bHLH-Zip transcription factors is only permissive when both factors contain either the same type of inserted stammer or no insert. Our data illustrate a unique principle of conditional partner selectivity within the wide arsenal of transcription factors with specific partner-dependent functional readouts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / chemistry*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Cell Nucleus / chemistry*
  • Ligands
  • Mice
  • Microphthalmia-Associated Transcription Factor / chemistry*
  • Microphthalmia-Associated Transcription Factor / genetics
  • Protein Binding
  • Protein Conformation*
  • Protein Domains / genetics
  • Protein Multimerization

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Ligands
  • Microphthalmia-Associated Transcription Factor
  • Mitf protein, mouse