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
SN - 0021-9258
VL - 280
SP - 32989
EP - 32996
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 38
ER -