Dimerization of doublesex is mediated by a cryptic ubiquitin-associated domain fold: Implications for sex-specific gene regulation

James R. Bayrer, Wei Zhang, Michael A. Weiss

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Male- and female-specific isoforms of the Doublesex (DSX) transcription factor regulate somatic sexual differentiation in Drosophila. The isoforms (DSXM and DSXF) share an N-terminal DNA binding domain (the DM motif), broadly conserved among metazoan sex-determining pathways. DM-DNA recognition is enhanced by a C-terminal dimerization domain. The crystal structure of this domain, determined at a resolution of 1.6 Å, reveals a novel dimeric arrangement of ubiquitin-associated (UBA) folds. Although this α-helical motif is well characterized in pathways of DNA repair and subcellular trafficking, to our knowledge this is its first report in a transcription factor. Dimerization is mediated by a non-canonical hydrophobic interface extrinsic to the putative ubiquitin binding surface. Key side chains at this interface, identified by alanine scanning mutagenesis, are conserved among DSX homologs. The mechanism of dimerization is thus unrelated to the low affinity domain swapping observed among ubiquitin-associated CUE domains. The unexpected observation of a ubiquitin-associated fold in DSX extends the repertoire of α-helical dimerization elements in transcription factors. The possibility that the ubiquitination machinery participates in the regulation of sexual dimorphism is discussed.

Original languageEnglish (US)
Pages (from-to)32989-32996
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number38
DOIs
StatePublished - Sep 23 2005

Fingerprint

Dimerization
Ubiquitin
Gene expression
Transcription Factors
Genes
DNA
Protein Isoforms
Sex Differentiation
Mutagenesis
Ubiquitination
Sex Characteristics
DNA Repair
Alanine
Drosophila
Machinery
Repair
Crystal structure
Observation
Scanning

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dimerization of doublesex is mediated by a cryptic ubiquitin-associated domain fold : Implications for sex-specific gene regulation. / Bayrer, James R.; Zhang, Wei; Weiss, Michael A.

In: Journal of Biological Chemistry, Vol. 280, No. 38, 23.09.2005, p. 32989-32996.

Research output: Contribution to journalArticle

@article{c3573d109fcd48b4b5bc4a821cdc3607,
title = "Dimerization of doublesex is mediated by a cryptic ubiquitin-associated domain fold: Implications for sex-specific gene regulation",
abstract = "Male- and female-specific isoforms of the Doublesex (DSX) transcription factor regulate somatic sexual differentiation in Drosophila. The isoforms (DSXM and DSXF) share an N-terminal DNA binding domain (the DM motif), broadly conserved among metazoan sex-determining pathways. DM-DNA recognition is enhanced by a C-terminal dimerization domain. The crystal structure of this domain, determined at a resolution of 1.6 {\AA}, reveals a novel dimeric arrangement of ubiquitin-associated (UBA) folds. Although this α-helical motif is well characterized in pathways of DNA repair and subcellular trafficking, to our knowledge this is its first report in a transcription factor. Dimerization is mediated by a non-canonical hydrophobic interface extrinsic to the putative ubiquitin binding surface. Key side chains at this interface, identified by alanine scanning mutagenesis, are conserved among DSX homologs. The mechanism of dimerization is thus unrelated to the low affinity domain swapping observed among ubiquitin-associated CUE domains. The unexpected observation of a ubiquitin-associated fold in DSX extends the repertoire of α-helical dimerization elements in transcription factors. The possibility that the ubiquitination machinery participates in the regulation of sexual dimorphism is discussed.",
author = "Bayrer, {James R.} and Wei Zhang and Weiss, {Michael A.}",
year = "2005",
month = "9",
day = "23",
doi = "10.1074/jbc.M507990200",
language = "English (US)",
volume = "280",
pages = "32989--32996",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "38",

}

TY - JOUR

T1 - Dimerization of doublesex is mediated by a cryptic ubiquitin-associated domain fold

T2 - Implications for sex-specific gene regulation

AU - Bayrer, James R.

AU - Zhang, Wei

AU - Weiss, Michael A.

PY - 2005/9/23

Y1 - 2005/9/23

N2 - Male- and female-specific isoforms of the Doublesex (DSX) transcription factor regulate somatic sexual differentiation in Drosophila. The isoforms (DSXM and DSXF) share an N-terminal DNA binding domain (the DM motif), broadly conserved among metazoan sex-determining pathways. DM-DNA recognition is enhanced by a C-terminal dimerization domain. The crystal structure of this domain, determined at a resolution of 1.6 Å, reveals a novel dimeric arrangement of ubiquitin-associated (UBA) folds. Although this α-helical motif is well characterized in pathways of DNA repair and subcellular trafficking, to our knowledge this is its first report in a transcription factor. Dimerization is mediated by a non-canonical hydrophobic interface extrinsic to the putative ubiquitin binding surface. Key side chains at this interface, identified by alanine scanning mutagenesis, are conserved among DSX homologs. The mechanism of dimerization is thus unrelated to the low affinity domain swapping observed among ubiquitin-associated CUE domains. The unexpected observation of a ubiquitin-associated fold in DSX extends the repertoire of α-helical dimerization elements in transcription factors. The possibility that the ubiquitination machinery participates in the regulation of sexual dimorphism is discussed.

AB - Male- and female-specific isoforms of the Doublesex (DSX) transcription factor regulate somatic sexual differentiation in Drosophila. The isoforms (DSXM and DSXF) share an N-terminal DNA binding domain (the DM motif), broadly conserved among metazoan sex-determining pathways. DM-DNA recognition is enhanced by a C-terminal dimerization domain. The crystal structure of this domain, determined at a resolution of 1.6 Å, reveals a novel dimeric arrangement of ubiquitin-associated (UBA) folds. Although this α-helical motif is well characterized in pathways of DNA repair and subcellular trafficking, to our knowledge this is its first report in a transcription factor. Dimerization is mediated by a non-canonical hydrophobic interface extrinsic to the putative ubiquitin binding surface. Key side chains at this interface, identified by alanine scanning mutagenesis, are conserved among DSX homologs. The mechanism of dimerization is thus unrelated to the low affinity domain swapping observed among ubiquitin-associated CUE domains. The unexpected observation of a ubiquitin-associated fold in DSX extends the repertoire of α-helical dimerization elements in transcription factors. The possibility that the ubiquitination machinery participates in the regulation of sexual dimorphism is discussed.

UR - http://www.scopus.com/inward/record.url?scp=25444460232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=25444460232&partnerID=8YFLogxK

U2 - 10.1074/jbc.M507990200

DO - 10.1074/jbc.M507990200

M3 - Article

C2 - 16049008

AN - SCOPUS:25444460232

VL - 280

SP - 32989

EP - 32996

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 38

ER -