Sexual dimorphism in diverse metazoans is regulated by a novel class of intertwined zinc fingers.
Sex determination is regulated by diverse pathways. Although upstream signals vary, a cysteine-rich DNA-binding domain (the DM motif) is conserved within downstream transcription factors of Drosophila melanogaster (Doublesex) and Caenorhabditis elegans (MAB-3). Vertebrate DM genes have likewise been identified and, remarkably, are associated with human sex reversal (46, XY gonadal dysgenesis). Here we demonstrate that the structure of the Doublesex domain contains a novel zinc module and disordered tail. The module consists of intertwined CCHC and HCCC Zn(2+)-binding sites; the tail functions as a nascent recognition alpha-helix. Mutations in either Zn(2+)-binding site or tail can lead to an intersex phenotype. The motif binds in the DNA minor groove without sharp DNA bending. These molecular features, unusual among zinc fingers and zinc modules, underlie the organization of a Drosophila enhancer that integrates sex- and tissue-specific signals. The structure provides a foundation for analysis of DM mutations affecting sexual dimorphism and courtship behavior.
Zhu
L
L
Center for Molecular Oncology, Departments of Biochemistry & Molecular Biology and Chemistry, The University of Chicago, Chicago, Illinois 60637-5419, USA.
Wilken
J
J
Phillips
N B
NB
Narendra
U
U
Chan
G
G
Stratton
S M
SM
Kent
S B
SB
Weiss
M A
MA
D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D002942:Circular Dichroism; D016384:Consensus Sequence; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D004330:Drosophila / Q000235:genetics* / Q000502:physiology; D029721:Drosophila Proteins; D005260:Female; D006860:Hydrogen Bonding; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012727:Sex Characteristics; D019849:Sex Determination Processes; D012726:Sexual Behavior, Animal; D014461:Ultracentrifugation; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C070369:DSX protein, Drosophila; D029721:Drosophila Proteins; D019476:Insect Proteins; D010455:Peptides; D004247:DNA; D015032:Zinc