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

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


Title: Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif
Author: Pogenberg, Vivian
Ballesteros-Álvarez, Josué
Schober, Romana
Sigvaldadóttir, Ingibjörg
Obarska-Kosinska, Agnieszka
Milewski, Morlin
Schindl, Rainer
Ögmundsdóttir, Margrét Helga
Steingrímsson, Eiríkur
Wilmanns, Matthias
Date: 2020-01-24
Language: English
Scope: 15
Department: Faculty of Medicine
Series: Nucleic Acids Research; 48(2)
ISSN: 0305-1048
DOI: https://doi.org/10.1093/nar/gkz1104
Subject: Prótín; Genetics
URI: https://hdl.handle.net/20.500.11815/3363

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Citation:

Pogenberg , V , Ballesteros-Álvarez , J , Schober , R , Sigvaldadóttir , I , Obarska-Kosinska , A , Milewski , M , Schindl , R , Ögmundsdóttir , M H , Steingrímsson , E & Wilmanns , M 2020 , ' Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif ' , Nucleic Acids Research , vol. 48 , no. 2 , pp. 934-948 . https://doi.org/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.

Description:

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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