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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Defective importin β recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations
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Defective importin β recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations

机译：性别决定因素SRY的输入蛋白β识别缺陷和核输入与XY性别反转突变有关

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摘要

The architectural transcription factor SRY (sex-determining region of the Y chromosome) plays a key role in sex determination as indicated by the fact that mutations in SRY are responsible for XY gonadal dysgenesis in humans. Although many SRY mutations reduce DNA-binding/bending activity, it is not clear how SRY mutations that do not affect interaction with DNA contribute to disease. The SRY high-mobility group domain harbors two nuclear localization signals (NLSs), and here we examine SRY from four XY females with missense mutations in these signals. In all cases, mutant SRY protein is partly localized to the cytoplasm, whereas wild-type SRY is strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins (IMPs) and requires unidentified cytoplasmic transport factors, whereas the C-terminal NLS is recognized by IMPβ. The SRY-R133W mutant shows reduced IMPβ binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the N-terminal NLS mutants examined, SRY-R62G unexpectedly shows a marked reduction in IMPβ binding, whereas SRY-R75N and SRY-R76P show normal IMPβ binding, suggesting defects in the IMP-independent pathway. We conclude that SRY normally requires the two distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. This study documents cases of human disease being explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus.
机译：结构性转录因子SRY（Y染色体的性别决定区）在性别决定中起着关键作用，这一事实表明，SRY中的突变可导致人类XY性腺发育不全。尽管许多SRY突变会降低DNA结合/弯曲活性，但尚不清楚不影响与DNA相互作用的SRY突变如何导致疾病。 SRY高迁移率族域包含两个核定位信号（NLSs），在这里，我们检查了来自这些信号中有错义突变的四位XY雌性的SRY。在所有情况下，突变型SRY蛋白都部分定位于细胞质，而野生型SRY则是严格的核型。每个NLS都可以在体外和体内独立地指导载体蛋白的核转运，而突变会影响核积累的速率和程度。 N末端NLS的功能独立于常规的NLS结合重要蛋白（IMP），并且需要未知的细胞质转运因子，而C末端NLS被IMPβ识别。 SRY-R133W突变体显示出IMPβ结合减少是性别逆转C端NLS突变的直接结果。在所检查的N端NLS突变体中，SRY-R62G出乎意料地显示出IMPβ结合的显着降低，而SRY-R75N和SRY-R76P表现出了正常的IMPβ结合，表明了IMP依赖性途径中的缺陷。我们得出的结论是，SRY通常需要两种不同的依赖NLS的核输入途径，才能在核中达到足够的水平来确定性别。这项研究从分子水平上解释了人类疾病的病例，这是由于蛋白质在细胞核中积累的能力受损所致。

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