ArticleThe Journal of biological chemistry2011
Mammalian testis-determining factor SRY and the enigma of inherited human sex reversal: frustrated induced fit in a bent protein-DNA complex.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- Solution structure of the Sox2 DNA-binding domain reveals conformational selection in DNA binding.Nucleic acids research · 2025Article
- Role of nucleobase-specific interactions in the binding and bending of DNA by human male sex determination factor SRY.The Journal of biological chemistry · 2024Article
- Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity.Frontiers in endocrinology · 2022Article
- Tenuous Transcriptional Threshold of Human Sex Determination. I. SRY and Swyer Syndrome at the Edge of Ambiguity.Frontiers in endocrinology · 2022Article
- Human Sex Determination at the Edge of Ambiguity: INHERITED XY SEX REVERSAL DUE TO ENHANCED UBIQUITINATION AND PROTEASOMAL DEGRADATION OF A MASTER TRANSCRIPTION FACTOR.The Journal of biological chemistry · 2016Article
- Structure-function relationships in human testis-determining factor SRY: an aromatic buttress underlies the specific DNA-bending surface of a high mobility group (HMG) box.The Journal of biological chemistry · 2014Article
- RevSex duplication-induced and sex-related differences in the SOX9 regulatory region chromatin landscape in human fibroblasts.Epigenetics · 2014Article
- Kinetics of fast changing intramolecular distance distributions obtained by combined analysis of FRET efficiency kinetics and time-resolved FRET equilibrium measurements.Biophysical journal · 2014Article
- Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- SRY protein function in sex determination: thinking outside the box.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2012Review
- Reprogramming cells with synthetic proteins.Asian journal of andrologyReview
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Mammalian testis-determining factor SRY contains a high mobility group box, a conserved eukaryotic motif of DNA bending. Mutations in SRY cause XY gonadal dysgenesis and somatic sex reversal. Although such mutations usually arise de novo in spermatogenesis, some are inherited and so specify male development in one genetic background (the father) but not another (the daughter). Here, we describe the biophysical properties of a representative inherited mutation, V60L, within the minor wing of the L-shaped domain (box position 5). Although the stability and DNA binding properties of the mutant domain are similar to those of wild type, studies of SRY-induced DNA bending by subnanosecond time-resolved fluorescence resonance energy transfer (FRET) revealed enhanced conformational fluctuations leading to long range variation in bend angle. (1)H NMR studies of the variant protein-DNA complex demonstrated only local perturbations near the mutation site. Because the minor wing of SRY folds on DNA binding, the inherited mutation presumably hinders induced fit. Stopped-flow FRET studies indicated that such frustrated packing leads to accelerated dissociation of the bent complex. Studies of SRY-directed transcriptional regulation in an embryonic gonadal cell line demonstrated partial activation of downstream target Sox9. Our results have demonstrated a nonlocal coupling between DNA-directed protein folding and protein-directed DNA bending. Perturbation of this coupling is associated with a genetic switch poised at the threshold of activity.
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