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

Vivian Pogenberg, Josué Ballesteros-Álvarez, Romana Schober, Ingibjörg Sigvaldadóttir, Agnieszka Obarska-Kosinska, Morlin Milewski, Rainer Schindl, Margrét Helga Ögmundsdóttir, Eiríkur Steingrímsson, Matthias Wilmanns*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)934-948
Number of pages15
JournalNucleic Acids Research
Volume48
Issue number2
DOIs
Publication statusPublished - 24 Jan 2020

Bibliographical note

Icelandic Research Fund [163413 to E.S. and M.H.Ö.]; Austrian Science Foundation [FWF P28701 to Ra.S.]. Funding for open access charge: Icelandic Research Fund [163413 to E.S. and M.H.Ö.]; Austrian Science Foundation [FWF P28701 to Ra.S.].

Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

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