Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity
Y-encoded transcription factor SRY initiates male differentiation in therian mammals. This factor contains a high-mobility-group (HMG) box, which mediates sequence-specific DNA binding with sharp DNA bending. A companion article in this issue described sex-reversal mutations at box position 72 (resi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.1029177/full |
| _version_ | 1811310373129682944 |
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| author | Joseph D. Racca Deepak Chatterjee Yen-Shan Chen Ratan K. Rai Yanwu Yang Millie M. Georgiadis Elisha Haas Michael A. Weiss |
| author_facet | Joseph D. Racca Deepak Chatterjee Yen-Shan Chen Ratan K. Rai Yanwu Yang Millie M. Georgiadis Elisha Haas Michael A. Weiss |
| author_sort | Joseph D. Racca |
| collection | DOAJ |
| description | Y-encoded transcription factor SRY initiates male differentiation in therian mammals. This factor contains a high-mobility-group (HMG) box, which mediates sequence-specific DNA binding with sharp DNA bending. A companion article in this issue described sex-reversal mutations at box position 72 (residue 127 in human SRY), invariant as Tyr among mammalian orthologs. Although not contacting DNA, the aromatic ring seals the domain’s minor wing at a solvent-exposed junction with a basic tail. A seeming paradox was posed by the native-like biochemical properties of inherited Swyer variant Y72F: its near-native gene-regulatory activity is consistent with the father’s male development, but at odds with the daughter’s XY female somatic phenotype. Surprisingly, aromatic rings (Y72, F72 or W72) confer higher transcriptional activity than do basic or polar side chains generally observed at solvated DNA interfaces (Arg, Lys, His or Gln). Whereas biophysical studies (time-resolved fluorescence resonance energy transfer and heteronuclear NMR spectroscopy) uncovered only subtle perturbations, dissociation of the Y72F complex was markedly accelerated relative to wild-type. Studies of protein-DNA solvation by molecular-dynamics (MD) simulations of an homologous high-resolution crystal structure (SOX18) suggest that Y72 para-OH anchors a network of water molecules at the tail-DNA interface, perturbed in the variant in association with nonlocal conformational fluctuations. Loss of the Y72 anchor among SRY variants presumably “unclamps” its basic tail, leading to (a) rapid DNA dissociation despite native affinity and (b) attenuated transcriptional activity at the edge of sexual ambiguity. Conservation of Y72 suggests that this water-mediated clamp operates generally among SRY and metazoan SOX domains. |
| first_indexed | 2024-04-13T09:57:48Z |
| format | Article |
| id | doaj.art-b100fc8439af4539b9f3a1c25f9920c3 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-13T09:57:48Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-b100fc8439af4539b9f3a1c25f9920c32022-12-22T02:51:20ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-12-011310.3389/fendo.2022.10291771029177Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguityJoseph D. Racca0Deepak Chatterjee1Yen-Shan Chen2Ratan K. Rai3Yanwu Yang4Millie M. Georgiadis5Elisha Haas6Michael A. Weiss7Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesFaculty of Life Sciences, Bar Ilan University, Ramat Gan, IsraelDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United StatesY-encoded transcription factor SRY initiates male differentiation in therian mammals. This factor contains a high-mobility-group (HMG) box, which mediates sequence-specific DNA binding with sharp DNA bending. A companion article in this issue described sex-reversal mutations at box position 72 (residue 127 in human SRY), invariant as Tyr among mammalian orthologs. Although not contacting DNA, the aromatic ring seals the domain’s minor wing at a solvent-exposed junction with a basic tail. A seeming paradox was posed by the native-like biochemical properties of inherited Swyer variant Y72F: its near-native gene-regulatory activity is consistent with the father’s male development, but at odds with the daughter’s XY female somatic phenotype. Surprisingly, aromatic rings (Y72, F72 or W72) confer higher transcriptional activity than do basic or polar side chains generally observed at solvated DNA interfaces (Arg, Lys, His or Gln). Whereas biophysical studies (time-resolved fluorescence resonance energy transfer and heteronuclear NMR spectroscopy) uncovered only subtle perturbations, dissociation of the Y72F complex was markedly accelerated relative to wild-type. Studies of protein-DNA solvation by molecular-dynamics (MD) simulations of an homologous high-resolution crystal structure (SOX18) suggest that Y72 para-OH anchors a network of water molecules at the tail-DNA interface, perturbed in the variant in association with nonlocal conformational fluctuations. Loss of the Y72 anchor among SRY variants presumably “unclamps” its basic tail, leading to (a) rapid DNA dissociation despite native affinity and (b) attenuated transcriptional activity at the edge of sexual ambiguity. Conservation of Y72 suggests that this water-mediated clamp operates generally among SRY and metazoan SOX domains.https://www.frontiersin.org/articles/10.3389/fendo.2022.1029177/fullDNA dynamicsnucleic-acid recognitionDNA intercalationprotein hydrationindirect readout |
| spellingShingle | Joseph D. Racca Deepak Chatterjee Yen-Shan Chen Ratan K. Rai Yanwu Yang Millie M. Georgiadis Elisha Haas Michael A. Weiss Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity Frontiers in Endocrinology DNA dynamics nucleic-acid recognition DNA intercalation protein hydration indirect readout |
| title | Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity |
| title_full | Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity |
| title_fullStr | Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity |
| title_full_unstemmed | Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity |
| title_short | Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity |
| title_sort | tenuous transcriptional threshold of human sex determination ii sry exploits water mediated clamp at the edge of ambiguity |
| topic | DNA dynamics nucleic-acid recognition DNA intercalation protein hydration indirect readout |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.1029177/full |
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