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首页> 外文期刊>Biochemistry >Structural Analysis of the Smad2—MANI Interaction That Regulates Transforming Growth Factor-β Signaling at the Inner Nuclear Membranet
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Structural Analysis of the Smad2—MANI Interaction That Regulates Transforming Growth Factor-β Signaling at the Inner Nuclear Membranet

机译：调节内核膜在内核膜上转化生长因子-β信号传导的SMAD2-MANI相互作用的结构分析

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摘要

MANI, an integral protein of the inner nuclear membrane, influences transforming growth factor-13 (TGF-11) signaling by directly interacting with R-Smads. Heterozygous loss of function mutations in the gene encoding MANI cause sclerosing hone dysplasias and an increased level of TGF-0 signaling in cells. As a first step in elucidating the mechanism of TGF-f3 pathway regulation by MANI, we characterized the structure of the MANI C-terminal region that binds Smad2. Using nuclear magnetic resonance spectroscopy,we observed that this region is comprised of a winged helix domain, a structurally heterogeneous linker, a U2AF homology motif (UHM) domain, and a disordered C-terminus. From nuclear magnetic resonance and smallangle X-ray scattering data, we calculated a family of' models for this MANI region. Our data indicate that the linker plays the role of an intramolecular UHM ligand motif (ULM) interacting with the UHM domain. We mapped the Smad2 binding site onto the MANI structure by combining GST pull-down,fluorescence, and yeast two-hybrid approaches. The linker region, the UHM domain, and the C-terminus are necessary for Smad2 binding with a micromolar affinity. Moreover, the intramolecular interaction between the linker and the UHM domain is critical for Smad2 binding. On the basis of the structural heterogeneity and binding properties of the linker, we suggest that it can interact with other UHM domains, thus regulating the MANI —Smad2 interaction.
机译：MANI是内核膜的整体蛋白，通过直接与R-Smads进行相互作用来影响转化生长因子-13（TGF-11）信号传导。编码MANI基因中的功能突变的杂合性损失导致硬化磨损的磨损磨损性和细胞中的TGF-0信号传导水平增加。作为阐明MANI的TGF-F3途径调节机理的第一步，我们表征了结合SMAD2的MANI C末端区域的结构。使用核磁共振光谱，我们观察到该区域由有翼的螺旋结构域，结构异构接头，U2AF同源基序（UHM）结构域和无序的C-末端组成。从核磁共振和Smalarangle X射线散射数据中，我们计算了一个“这个漫画地区的模型”。我们的数据表明，接头起到与UHM结构域相互作用的分子内UHM配体基序（ULM）的作用。通过组合GST下拉，荧光和酵母双混合方法将Smad2结合部位映射到Mani结构上。与微摩尔亲和力的Smad2结合需要接头区域，UHM结构域和C末端。此外，接头和UHM结构域之间的分子内相互作用对于Smad2结合至关重要。在接头的结构异质性和结合特性的基础上，我们建议它可以与其他UHM结构域相互作用，从而调节MANI -SMAD2的相互作用。

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  • 来源
    《Biochemistry》 |2010年第37期|共13页
  • 作者

    Emilie Konde; Benjamin Bourgeois; Carine Tellier-Lebegue; Wei Wu; Javier Perez; Sandrine Caputo; Wika Attanda; Sylvaine Gasparini; Jean-Baptiste Charbonnier; Bernard Gilquin; Howard J. Worman; Sophie Zinn-Justin;

  • 作者单位

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Department of Medicine and Department of Pathology and Cell Biology College of Physicians and Surgeons Columbia University New York New York 10032;

    Synchrotron SOLEIL BP 48 91192 Gif-sur-Yvette Cedex Prance;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

    Lahoraroire de Biologie Structurale et Radiobiologie URA CN RS 2096 CEA Saclay 91190 Gif-sur-Y vette France;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

    domain; magnetic; combining;

    机译：领域;磁性;结合;

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