| Structural highlights
Disease
SRY_HUMAN Defects in SRY are the cause of 46,XY sex reversal type 1 (SRXY1) [MIM:400044. A condition characterized by male-to-female sex reversal in the presence of a normal 46,XY karyotype. Patients manifest rapid and early degeneration of their gonads, which are present in the adult as 'streak gonads', consisting mainly of fibrous tissue and variable amounts of ovarian stroma. As a result these patients do not develop secondary sexual characteristics at puberty. The external genitalia in these subjects are completely female, and Muellerian structures are normal.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [:][14] [15] [16] [17] [:][18] [19] [20] [21] [22] [23] Note=A 45,X chromosomal aberration involving SRY is found in Turner syndrome, a disease characterized by gonadal dysgenesis with short stature, "streak gonads", variable abnormalities such as webbing of the neck, cubitus valgus, cardiac defects, low posterior hair line. The phenotype is female. Defects in SRY are the cause of 46,XX sex reversal type 1 (SRXX1) [MIM:400045. A condition in which male gonads develop in a genetic female (female to male sex reversal).[24] [25]
Function
SRY_HUMAN Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells (By similarity). In male adult brain involved in the maintenance of motor functions of dopaminergic neurons (By similarity). Involved in different aspects of gene regulation including promoter activation or repression (By similarity). Promotes DNA bending. SRY HMG box recognizes DNA by partial intercalation in the minor groove. Also involved in pre-mRNA splicing. Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3'.[26] [27] [28] [29]
Publication Abstract from PubMed
Y-chromosome-encoded master transcription factor SRY functions in the embryogenesis of therian mammals to initiate male development. Through interactions of its conserved high-mobility group box within a widened DNA minor groove, SRY and related Sox factors induce sharp bends at specific DNA target sites. Here, we present the crystal structure of the SRY high-mobility group domain bound to a DNA site containing consensus element 5'-ATTGTT. The structure contains three complexes in the asymmetric unit; in each complex, SRY forms 10 hydrogen bonds with minor-groove base atoms in 5'-CATTGT/ACAATG-3', shifting the recognition sequence by one base pair (italics). These nucleobase interactions involve conserved residues Arg7, Asn10, and Tyr74 on one side of intercalated Ile13 (the cantilever) and Arg20, Asn32, and Ser36 on the other. Unlike the less-bent NMR structure, DNA bend angles (69-84 degrees ) of the distinct box-DNA complexes are similar to those observed in homologous Sox domain-DNA structures. Electrophoretic studies indicate that respective substitutions of Asn32, Ser36, or Tyr74 by Ala exhibit slightly attenuated specific DNA-binding affinity and bend angles (70-73 degrees ) relative to WT (79 degrees ). By contrast, respective substitutions of Arg7, Asn10, or Arg20 by Ala markedly impaired DNA-binding affinity in association with much smaller DNA bend angles (53-65 degrees ). In a rodent cell-based model of the embryonic gonadal ridge, full-length SRY variants bearing these respective Ala substitutions exhibited significantly decreased transcriptional activation of SRY's principal target gene (Sox9). Together, our findings suggest that nucleobase-specific hydrogen bonds by SRY are critical for specific DNA binding, bending, and transcriptional activation.
Role of nucleobase-specific interactions in the binding and bending of DNA by human male sex determination factor SRY.,Racca JD, Chen YS, Brabender AR, Battistin U, Weiss MA, Georgiadis MM J Biol Chem. 2024 Aug 20;300(9):107683. doi: 10.1016/j.jbc.2024.107683. PMID:39168182[30]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:https://dx.doi.org/10.1006/jmbi.2001.4977
- ↑ Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M. Genetic evidence equating SRY and the testis-determining factor. Nature. 1990 Nov 29;348(6300):448-50. PMID:2247149 doi:https://dx.doi.org/10.1038/348448A0
- ↑ Affara NA, Chalmers IJ, Ferguson-Smith MA. Analysis of the SRY gene in 22 sex-reversed XY females identifies four new point mutations in the conserved DNA binding domain. Hum Mol Genet. 1993 Jun;2(6):785-9. PMID:8353496
- ↑ Vilain E, McElreavey K, Jaubert F, Raymond JP, Richaud F, Fellous M. Familial case with sequence variant in the testis-determining region associated with two sex phenotypes. Am J Hum Genet. 1992 May;50(5):1008-11. PMID:1570829
- ↑ Hawkins JR, Taylor A, Goodfellow PN, Migeon CJ, Smith KD, Berkovitz GD. Evidence for increased prevalence of SRY mutations in XY females with complete rather than partial gonadal dysgenesis. Am J Hum Genet. 1992 Nov;51(5):979-84. PMID:1415266
- ↑ Hawkins JR, Taylor A, Berta P, Levilliers J, Van der Auwera B, Goodfellow PN. Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471-4. PMID:1339396
- ↑ Braun A, Kammerer S, Cleve H, Lohrs U, Schwarz HP, Kuhnle U. True hermaphroditism in a 46,XY individual, caused by a postzygotic somatic point mutation in the male gonadal sex-determining locus (SRY): molecular genetics and histological findings in a sporadic case. Am J Hum Genet. 1993 Mar;52(3):578-85. PMID:8447323
- ↑ Jager RJ, Harley VR, Pfeiffer RA, Goodfellow PN, Scherer G. A familial mutation in the testis-determining gene SRY shared by both sexes. Hum Genet. 1992 Dec;90(4):350-5. PMID:1483689
- ↑ Zeng YT, Ren ZR, Zhang ML, Huang Y, Zeng FY, Huang SZ. A new de novo mutation (A113T) in HMG box of the SRY gene leads to XY gonadal dysgenesis. J Med Genet. 1993 Aug;30(8):655-7. PMID:8105086
- ↑ Poulat F, Soullier S, Goze C, Heitz F, Calas B, Berta P. Description and functional implications of a novel mutation in the sex-determining gene SRY. Hum Mutat. 1994;3(3):200-4. PMID:8019555 doi:https://dx.doi.org/10.1002/humu.1380030305
- ↑ Haqq CM, King CY, Ukiyama E, Falsafi S, Haqq TN, Donahoe PK, Weiss MA. Molecular basis of mammalian sexual determination: activation of Mullerian inhibiting substance gene expression by SRY. Science. 1994 Dec 2;266(5190):1494-500. PMID:7985018
- ↑ Schmitt-Ney M, Thiele H, Kaltwasser P, Bardoni B, Cisternino M, Scherer G. Two novel SRY missense mutations reducing DNA binding identified in XY females and their mosaic fathers. Am J Hum Genet. 1995 Apr;56(4):862-9. PMID:7717397
- ↑ Hiort O, Gramss B, Klauber GT. True hermaphroditism with 46,XY karyotype and a point mutation in the SRY gene. J Pediatr. 1995 Jun;126(6):1022. PMID:7776083
- ↑ Scherer G, Held M, Erdel M, Meschede D, Horst J, Lesniewicz R, Midro AT. Three novel SRY mutations in XY gonadal dysgenesis and the enigma of XY gonadal dysgenesis cases without SRY mutations. Cytogenet Cell Genet. 1998;80(1-4):188-92. PMID:9678356
- ↑ Domenice S, Yumie Nishi M, Correia Billerbeck AE, Latronico AC, Aparecida Medeiros M, Russell AJ, Vass K, Marino Carvalho F, Costa Frade EM, Prado Arnhold IJ, Bilharinho Mendonca B. A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives. Hum Genet. 1998 Feb;102(2):213-5. PMID:9521592
- ↑ Dork T, Stuhrmann M, Miller K, Schmidtke J. Independent observation of SRY mutation I90M in a patient with complete gonadal dysgenesis. Hum Mutat. 1998;11(1):90-1. PMID:9450909 doi:<90::AID-HUMU14>3.0.CO;2-U 10.1002/(SICI)1098-1004(1998)11:1<90::AID-HUMU14>3.0.CO;2-U
- ↑ Imai A, Takagi A, Tamaya T. A novel sex-determining region on Y (SRY) missense mutation identified in a 46,XY female and also in the father. Endocr J. 1999 Oct;46(5):735-9. PMID:10670762
- ↑ Schaffler A, Barth N, Winkler K, Zietz B, Rummele P, Knuchel R, Scholmerich J, Palitzsch KD. Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor. J Clin Endocrinol Metab. 2000 Jun;85(6):2287-92. PMID:10852465
- ↑ Canto P, de la Chesnaye E, Lopez M, Cervantes A, Chavez B, Vilchis F, Reyes E, Ulloa-Aguirre A, Kofman-Alfaro S, Mendez JP. A mutation in the 5' non-high mobility group box region of the SRY gene in patients with Turner syndrome and Y mosaicism. J Clin Endocrinol Metab. 2000 May;85(5):1908-11. PMID:10843173
- ↑ Okuhara K, Tajima T, Nakae J, Fujieda K. A novel missense mutation in the HMG box region of the SRY gene in a Japanese patient with an XY sex reversal. J Hum Genet. 2000;45(2):112-4. PMID:10721678 doi:10.1007/s100380050026
- ↑ Jordan BK, Jain M, Natarajan S, Frasier SD, Vilain E. Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father. J Clin Endocrinol Metab. 2002 Jul;87(7):3428-32. PMID:12107262
- ↑ Maier EM, Leitner C, Lohrs U, Kuhnle U. True hermaphroditism in an XY individual due to a familial point mutation of the SRY gene. J Pediatr Endocrinol Metab. 2003 Apr-May;16(4):575-80. PMID:12793612
- ↑ Gimelli G, Gimelli S, Dimasi N, Bocciardi R, Di Battista E, Pramparo T, Zuffardi O. Identification and molecular modelling of a novel familial mutation in the SRY gene implicated in the pure gonadal dysgenesis. Eur J Hum Genet. 2007 Jan;15(1):76-80. Epub 2006 Oct 25. PMID:17063144 doi:10.1038/sj.ejhg.5201719
- ↑ Inoue H, Nomura M, Yanase T, Ichino I, Goto K, Ikuyama S, Takayanagi R, Nawata H. A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determining region Y chromosome-bearing cells in the gonads. Intern Med. 1998 May;37(5):467-71. PMID:9652903
- ↑ Margarit E, Coll MD, Oliva R, Gomez D, Soler A, Ballesta F. SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite. Am J Med Genet. 2000 Jan 3;90(1):25-8. PMID:10602113
- ↑ Ohe K, Lalli E, Sassone-Corsi P. A direct role of SRY and SOX proteins in pre-mRNA splicing. Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1146-51. Epub 2002 Jan 29. PMID:11818535 doi:10.1073/pnas.022645899
- ↑ Phillips NB, Nikolskaya T, Jancso-Radek A, Ittah V, Jiang F, Singh R, Haas E, Weiss MA. Sry-directed sex reversal in transgenic mice is robust with respect to enhanced DNA bending: comparison of human and murine HMG boxes. Biochemistry. 2004 Jun 8;43(22):7066-81. PMID:15170344 doi:10.1021/bi049920a
- ↑ Li B, Phillips NB, Jancso-Radek A, Ittah V, Singh R, Jones DN, Haas E, Weiss MA. SRY-directed DNA bending and human sex reversal: reassessment of a clinical mutation uncovers a global coupling between the HMG box and its tail. J Mol Biol. 2006 Jul 7;360(2):310-28. Epub 2006 May 9. PMID:16762365 doi:S0022-2836(06)00522-5
- ↑ Murphy EC, Zhurkin VB, Louis JM, Cornilescu G, Clore GM. Structural basis for SRY-dependent 46-X,Y sex reversal: modulation of DNA bending by a naturally occurring point mutation. J Mol Biol. 2001 Sep 21;312(3):481-99. PMID:11563911 doi:https://dx.doi.org/10.1006/jmbi.2001.4977
- ↑ Racca JD, Chen YS, Brabender AR, Battistin U, Weiss MA, Georgiadis MM. Role of nucleobase-specific interactions in the binding and bending of DNA by human male sex determination factor SRY. J Biol Chem. 2024 Aug 20;300(9):107683. PMID:39168182 doi:10.1016/j.jbc.2024.107683
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