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首页> 外文期刊>Journal of Molecular Biology >Defining the molecular basis of Arf and Hdm2 interactions.
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Defining the molecular basis of Arf and Hdm2 interactions.

机译：定义Arf和Hdm2相互作用的分子基础。

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Understanding the interaction of Arf and Hdm2 has recently become a central issue in cancer biology. In response to hyperproliferative signals, p14(Arf) stabilizes p53 by binding to Hdm2 and inhibits the ubiquitination and subsequent proteosome-dependent degradation of p53. The medical importance of the Arf-Hdm2-p53 regulatory system is highlighted by the finding that either p53 or p14(Arf) are lost or modified in virtually all human cancers. Isolated Arf and Hdm2 domains are dynamically disordered in solution, yet they retain the ability to interact in vitro and in cellular assays. Upon binding, domains of both Arf and Hdm2 undergo a dramatic transition from disordered conformations to extended structures comprised of beta-strands. The presence of domains from both proteins are necessary and sufficient for the formation of the highly stable extended beta structures. We have mapped sites within Arf and Hdm2 that interact at a resolution of five amino acid residues using surface plasmon resonance. Surface plasmon resonance and circular dichroism spectropolarimetry confirm the presence of multiple interaction domains within each protein. Both p14(Arf) (human) and p19(Arf) (mouse) interact with Hdm2 through two short motifs present in their N termini. The Arf interacting region of Hdm2 is also composed of two short sequences located in the central acidic domain, between residues 235-264 and 270-289. The binding-induced structural transition is also induced by short peptides, 15 amino acids in length, that contain the binding motifs. Micro-injection and live cell imaging of proteins tagged with fluorescent labels was used to confirm the in vivo function of the interaction domains. Arf and Hdm2 thus appear to interact through a novel mechanism that exerts control over the cell division cycle. The novel molecular mechanism of interaction and the limited size of the protein domains involved provide opportunities for the development of anticancer therapeutics.
机译：最近，了解Arf和Hdm2的相互作用已成为癌症生物学的中心问题。响应过度增殖的信号，p14（Arf）通过与Hdm2结合来稳定p53，并抑制p53的泛素化和随后的蛋白体依赖性降解。发现p53或p14（Arf）在几乎所有人类癌症中都会丢失或修饰，这突显了Arf-Hdm2-p53调控系统的医学重要性。分离的Arf和Hdm2域在溶液中是动态无序的，但它们仍具有在体外和细胞测定中相互作用的能力。结合后，Arf和Hdm2的结构域都经历了从无序构象到由β链组成的延伸结构的急剧转变。来自两种蛋白质的结构域的存在对于形成高度稳定的扩展β结构而言是必要的，也是足够的。我们已经绘制了Arf和Hdm2内的位点，这些位点使用表面等离振子共振以五个氨基酸残基的分辨率相互作用。表面等离振子共振和圆二色性光谱极谱法证实了每种蛋白质中存在多个相互作用域。 p14（Arf）（人类）和p19（Arf）（小鼠）都通过其N末端存在的两个短基元与Hdm2相互作用。 Hdm2的Arf相互作用区域还由位于中央酸性域中残基235-264和270-289之间的两个短序列组成。结合诱导的结构转变也由包含结合基序的长度为15个氨基酸的短肽诱导。微注射和活细胞成像的荧光标记标签的蛋白质被用来确认相互作用域的体内功能。因此，Arf和Hdm2似乎是通过一种对细胞分裂周期施加控制的新型机制相互作用的。相互作用的新型分子机制和所涉及的蛋白质结构域的有限大小为开发抗癌疗法提供了机会。

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