DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.
DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.
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DOI：
10.1016/j.cell.2011.01.013
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发表时间：
2011-02-18
期刊：
影响因子：
64.5
通讯作者：
Dötsch V
中科院分区：
文献类型：
--
作者：
Deutsch GB;Zielonka EM;Coutandin D;Weber TA;Schäfer B;Hannewald J;Luh LM;Durst FG;Ibrahim M;Hoffmann J;Niesen FH;Sentürk A;Kunkel H;Brutschy B;Schleiff E;Knapp S;Acker-Palmer A;Grez M;McKeon F;Dötsch V
TAp 63 α是p53肿瘤抑制因子的同源物，是女性生殖系中的质量控制因子。值得注意的是，已经未受损的卵母细胞表达高水平的蛋白质，这表明TAp 63 α的活性受到抑制机制的严格控制。生物化学研究已经提出抑制作用需要C-末端反式激活抑制结构域。然而，TAp 63 α抑制的结构机制仍然未知。在这里，我们表明TAp 63 α保持在无活性的二聚体状态。我们发现，抑制的缓解导致四聚体形成与1020倍更高的DNA亲和力。在体内，磷酸化触发的TAp 63 α四聚体不能通过去磷酸化逆转。此外，我们表明，螺旋的寡聚化结构域的p63是至关重要的四聚体稳定和竞争的反式激活结构域相同的结合位点。我们的研究结果证明了TAp 63 α是如何被复杂的结构域-结构域相互作用抑制的，这为卵母细胞的质量控制提供了基础。TAp 63 α在二聚体状态下被复杂的结构域-结构域相互作用抑制。DNA损伤后磷酸化触发的TAp 63 α活化需要四聚化。四聚体稳定需要四聚化结构域的第二个螺旋H2。
TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes. ► TAp63α is inhibited in a dimeric state by complex domain-domain interactions ► Phosphorylation-triggered TAp63α activation upon DNA damage requires tetramerization ► Tetramer stabilization requires the second helix H2 of the tetramerization domain ► Tetramerization domain binding by the transactivation domain is competed by helix H2
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影响因子：
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作者：
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通讯作者：
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影响因子：
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DOI：
10.1073/pnas.0900383106
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影响因子：
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DOI：
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发表时间：
2007-08-01
影响因子：
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