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首页> 外文期刊>Journal of Molecular Biology >Structural Conservation and E2F Binding Specificity within the Retinoblastoma Pocket Protein Family
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Structural Conservation and E2F Binding Specificity within the Retinoblastoma Pocket Protein Family

机译：视网膜母细胞瘤口袋蛋白家族中的结构保守性和E2F结合特异性

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摘要

The human pocket proteins retinoblastoma (Rb), p107, and p130 are critical negative regulators of the cell cycle and contribute to tumor suppression. While strong structural conservation within the pocket protein family provides for some functional redundancy, important differences have been observed and may underlie the reason that Rb is a uniquely potent tumor suppressor. It has been proposed that distinct pocket protein activities are mediated by their different E2F transcription factor binding partners. In humans, Rb binds E2F1-E2F5, whereas p107 and p130 almost exclusively associate with E2F4 and E2F5. To identify the molecular determinants of this specificity, we compared the crystal structures of Rb and p107 pocket domains and identified several key residues that contribute to E2F selectivity in the pocket family. Mutation of these residues in p107 to match the analogous residue in Rb results in an increase in affinity for E2F1 and E2F2 and an increase in the ability of p107 to inhibit E2F2 transactivation. Additionally, we investigated how phosphorylation by Cyclin-dependent kinase on distinct residues regulates p107 affinity for the E2F4 transactivation domain. We found that phosphorylation of residues S650 and S975 weakens the E2F4 transactivation domain binding. Our data reveal molecular features of pocket proteins that are responsible for their similarities and differences in function and regulation. (C) 2016 Elsevier Ltd. All rights reserved.
机译：人口袋蛋白视网膜母细胞瘤（Rb），p107和p130是细胞周期的关键负调控因子，有助于抑制肿瘤。尽管口袋蛋白家族中强大的结构保守性提供了某些功能冗余，但已观察到重要的差异，这可能是Rb是独特有效的肿瘤抑制因子的原因。已经提出不同的口袋蛋白活性是由它们不同的E2F转录因子结合伴侣介导的。在人类中，Rb结合E2F1-E2F5，而p107和p130几乎仅与E2F4和E2F5缔合。为了确定这种特异性的分子决定因素，我们比较了Rb和p107口袋域的晶体结构，并鉴定了几个有助于口袋家族中E2F选择性的关键残基。 p107中这些残基的突变以匹配Rb中的类似残基导致对E2F1和E2F2的亲和力增加，并且p107抑制E2F2反式激活的能力增强。此外，我们研究了细胞周期蛋白依赖性激酶在不同残基上的磷酸化如何调节E2F4反式激活域的p107亲和力。我们发现，残基S650和S975的磷酸化会削弱E2F4反式激活域的结合。我们的数据揭示了口袋蛋白的分子特征，这些特征负责它们在功能和调节方面的相似性和差异。 （C）2016 Elsevier Ltd.保留所有权利。

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