Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif. Issue 2 (28th November 2019)

• Record Type: Journal Article
• Authors: Pogenberg, Vivian; Ballesteros-Álvarez, Josué; Schober, Romana; Sigvaldadóttir, Ingibjörg; Obarska-Kosinska, Agnieszka; Milewski, Morlin; Schindl, Rainer; Ögmundsdóttir, Margrét Helga; Steingrímsson, Eiríkur; Wilmanns, Matthias
• Is Part Of: Nucleic acids research. Volume 48:Issue 2(2020)
• Page Start: 934
• Page End: 948
• Publication Date: 2019-11-28
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkz1104
• Languages: English
• ISSNs: 0305-1048

Abstract

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.