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Hypersensitive termination of the hypoxic response by a disordered protein switch

机译：蛋白质开关紊乱导致缺氧反应的超敏性终止

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摘要

The cellular response to hypoxia is critical for cell survival and is fine-tuned to allow cells to recover from hypoxic stress and adapt to heterogeneous or fluctuating oxygen levels(1,2). The hypoxic response is mediated by the a-subunit of the transcription factor HIF-1 (HIF-1 alpha)(3), which interacts through its intrinsically disordered C-terminal transactivation domain with the TAZ1 (also known as CH1) domain of the general transcriptional coactivators CBP and p300 to control the transcription of critical adaptive genes(4-6). One such gene encodes CITED2, a negative feedback regulator that attenuates HIF-1 transcriptional activity by competing for TAZ1 binding through its own disordered transactivation domain(7-9). Little is known about the molecular mechanism by which CITED2 displaces the tightly bound HIF-1 alpha from their common cellular target. The HIF-1 alpha and CITED2 transactivation domains bind to TAZ1 through helical motifs that flank a conserved LP(Q/ E) L sequence that is essential for negative feedback regulation(5,6,8,9). Here we show that human CITED2 displaces HIF-1 alpha by forming a transient ternary complex with TAZ1 and HIF-1 alpha and competing for a shared binding site through its LPEL motif, thus promoting a conformational change in TAZ1 that increases the rate of HIF-1 alpha dissociation. Through allosteric enhancement of HIF-1 alpha release, CITED2 activates a highly responsive negative feedback circuit that rapidly and efficiently attenuates the hypoxic response, even at modest CITED2 concentrations. This hypersensitive regulatory switch is entirely dependent on the unique flexibility and binding properties of these intrinsically disordered proteins and probably exemplifies a common strategy used by the cell to respond rapidly to environmental signals.
机译：细胞对低氧的反应对于细胞存活至关重要，并进行了微调以使细胞从低氧应激中恢复并适应氧的含量不均或波动（1,2）。低氧反应是由转录因子HIF-1（HIF-1 alpha）（3）的a亚基介导的，该亚基通过其内在无序的C末端反式激活结构域与TAZ1（也称为CH1）结构域相互作用。一般的转录共激活因子CBP和p300可控制关键适应基因的转录（4-6）。一个这样的基因编码CITED2，它是一种负反馈调节剂，通过其自身无序的反式激活结构域竞争TAZ1结合，从而减弱HIF-1转录活性（7-9）。关于CITED2从其共同的细胞靶位置换紧密结合的HIF-1α的分子机制，人们所知甚少。 HIF-1α和CITED2反式激活域通过螺旋基序与TAZ1结合，该基序位于保守的LP（Q / E）L序列的侧面，这对负反馈调节至关重要（5、6、8、9）。在这里，我们显示人类CITED2通过与TAZ1和HIF-1 alpha形成瞬时三元复合物并通过其LPEL基序竞争共享的结合位点来取代HIF-1 alpha，从而促进了TAZ1的构象变化，从而增加了HIF- 1 alpha解离。通过HIF-1α释放的变构增强，即使在适度的CITED2浓度下，CITED2仍可激活高响应负反馈电路，该电路可快速有效地减弱低氧反应。这种超敏调节开关完全取决于这些内在失调的蛋白质的独特灵活性和结合特性，并且可能例举了细胞用于快速响应环境信号的通用策略。

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  • 来源
    《Nature》 |2017年第7645期|447-451|共5页
  • 作者

    Berlow Rebecca B.; Dyson H. Jane; Wright Peter E.;

  • 作者单位

    Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA|Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA;

    Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA|Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA;

    Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA|Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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