Bayrer James R, Zhang Wei, Weiss Michael A
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
J Biol Chem. 2005 Sep 23;280(38):32989-96. doi: 10.1074/jbc.M507990200. Epub 2005 Jul 27.
Male- and female-specific isoforms of the Doublesex (DSX) transcription factor regulate somatic sexual differentiation in Drosophila. The isoforms (DSX(M) and DSX(F)) 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 A, reveals a novel dimeric arrangement of ubiquitin-associated (UBA) folds. Although this alpha-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 alpha-helical dimerization elements in transcription factors. The possibility that the ubiquitination machinery participates in the regulation of sexual dimorphism is discussed.
双性（DSX）转录因子的雄性和雌性特异性同工型调节果蝇的体细胞性别分化。这些同工型（DSX(M)和DSX(F)）共享一个N端DNA结合结构域（DM基序），该结构域在后生动物性别决定途径中广泛保守。DM与DNA的识别通过C端二聚化结构域得到增强。该结构域的晶体结构在1.6 Å的分辨率下确定，揭示了泛素相关（UBA）折叠的一种新型二聚体排列。尽管这种α螺旋基序在DNA修复和亚细胞运输途径中已得到充分表征，但据我们所知，这是其在转录因子中的首次报道。二聚化由假定的泛素结合表面外部的非经典疏水界面介导。通过丙氨酸扫描诱变确定的该界面处的关键侧链在DSX同源物中保守。因此，二聚化机制与在泛素相关CUE结构域中观察到的低亲和力结构域交换无关。在DSX中意外观察到泛素相关折叠扩展了转录因子中α螺旋二聚化元件的种类。本文还讨论了泛素化机制参与性别二态性调节的可能性。
