Sex-reversing mutations affect the architecture of SRY-DNA complexes.
The testis determining factor, SRY, is a DNA binding protein that causes a large distortion of its DNA target sites. We have analysed the biochemical properties of the DNA binding domains (HMG-boxes) of mutant SRY proteins from five patients with complete gonadal dysgenesis. The mutant proteins fall into three categories: two bind and bend DNA almost normally, two bind inefficiently but bend DNA normally and one binds DNA with almost normal affinity but produces a different angle. The mutations with moderate effect on complex formation can be transmitted to male progeny, the ones with severe effects on either binding or bending are de novo. The angle induced by SRY depends on the exact DNA sequence and thus adds another level of discrimination in target site recognition. These data suggest that the exact spatial arrangement of the nucleoprotein complex organized by SRY is essential for sex determination.
Pontiggia
A
A
DIBIT, San Raffaele Scientific Institute, Milano, Italy.
Rimini
R
R
Harley
V R
VR
Goodfellow
P N
PN
Lovell-Badge
R
R
Bianchi
M E
ME
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D006059:Gonadal Dysgenesis / Q000235:genetics*; D006609:High Mobility Group Proteins; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D051876:Sex-Determining Region Y Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D009687:Nuclear Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors; D004247:DNA