Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination

Liang Zhao; Ee Ting Ng; Tara-Lynne DavidsonEnya LongmussJohann UrschitzMarlee ElstonStefan MoisyadiJosephine BowlesPeter Koopman

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Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination

机译：Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination

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The mammalian sex-determining factor SRY comprises a conserved high-mobility group (HMG) box DNA-binding domain and poorly conserved regions outside the HMG box. Mouse Sry is unusual in that it includes a C-terminal polyglutamine (polyQ) tract that is absent in nonrodent SRY proteins, and yet, paradoxically, is essential for male sex determination. To dissect the molecular functions of this domain, we generated a series of Sry mutants, and studied their biochemical properties in cell lines and transgenic mouse embryos. Sry protein lacking the polyQ domain was unstable, due to proteasomal degradation. Replacing this domain with irrelevant sequences stabilized the protein but failed to restore Sry's ability to up-regulate its key target gene SRY-box 9 (Sox9) and its sex-determining function in vivo. These functions were restored only when a VP16 transactivation domain was substituted. We conclude that the polyQ domain has important roles in protein stabilization and transcriptional activation, both of which are essential for male sex determination in mice. Our data disprove the hypothesis that the conserved HMG box domain is the only functional domain of Sry, and highlight an evolutionary paradox whereby mouse Sry has evolved a novel bifunctional module to activate Sox9 directly, whereas SRY proteins in other taxa, including humans, seem to lack this ability, presumably making them dependent on partner proteins(s) to provide this function.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第32期|11768-11773|共6页
作者
Liang Zhao; Ee Ting Ng; Tara-Lynne DavidsonEnya LongmussJohann UrschitzMarlee ElstonStefan MoisyadiJosephine BowlesPeter Koopman;
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作者单位

Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia;

Institute for Biogenesis Research, Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96822;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
sex development; Y chromosome; testis; TESCO;

Structure-function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination

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