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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease
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Functional and structural characterization of a dense core secretory granule sorting domain from the PC1/3 protease

机译：从PC1 / 3蛋白酶的致密核心分泌颗粒分选域的功能和结构表征

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摘要

Several peptide hormones are initially synthesized as inactive precursors. It is only on entry of these prohormones and their processing proteases into dense core secretory granules (DCSGs) that the precursors are cleaved to generate their active forms. Prohormone convertase (PC)1/3 is a processing protease that is targeted to DCSGs. The signal for targeting PC1/3 to DCSGs resides in its carboxy-terminal tail (PC1/3_(617-753)), where 3 regions (PC1/ 3_(617-625), PC1/3_(665-682), and PCI/3_(711-753)) are known to aid in sorting and membrane association. In this article, we have determined a high-resolution structure of the extreme carboxy-terminal sorting domain, PC1/3_(711-753 in micelles by NMR spectroscopy. PCI/3_(711-753) contains 2 alpha helices located between residues 722-728 and 738-750. Functional assays demonstrate that the second helix (PC1/3_(738-750)) is necessary and sufficient to target a constitutively secreted protein to granules, and that L~(745) anchors a hydrophobic patch that is critical for sorting. Also, we demonstrate that calcium binding by the second helix of PC1/3_(711-753) promotes aggregation of the domain via the hydrophobic patch centered on L~(745). These results provide a structure-function analysis of a DCSG-sorting domain, and reveal the importance of a hydrophobic patch and calcium binding in controlling the sorting of proteins containing alpha helices to DCSGs.
机译：最初合成了几种肽激素作为无活性的前体。仅在这些激素和它们的加工蛋白酶进入致密核心分泌颗粒（DCSG）中时，才将前体裂解以产生其活性形式。激素原转化酶（PC）1/3是一种针对DCSG的加工蛋白酶。将PC1 / 3靶向DCSG的信号位于其羧基末端尾巴（PC1 / 3_（617-753）），其中3个区域（PC1 / 3_（617-625），PC1 / 3_（665-682）和已知PCI / 3_（711-753））有助于分类和膜结合。在本文中，我们通过NMR光谱确定了极端羧基末端分选结构域PC1 / 3_（711-753在胶束中的高分辨率结构。PCI/ 3_（711-753）包含位于残基722之间的2个α螺旋。 -728和738-750。功能分析表明，第二个螺旋（PC1 / 3_（738-750））是必要且足以将组成型分泌蛋白靶向颗粒的，而L〜（745）锚定了一个疏水性斑块此外，我们证明了PC1 / 3_（711-753）第二个螺旋与钙的结合通过以L〜（745）为中心的疏水性补丁促进了结构域的聚集，这些结果提供了对结构的功能分析。 DCSG分选域，并揭示了疏水性补丁和钙结合在控制含α螺旋的蛋白质到DCSG的分选中的重要性。

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    Jimmy D. Dikeakos; Paola Di Lello; Marie-Josee Lacombe; Rodolfo Ghirlando; Pascale Legault; Timothy L. Reudelhuber; James G. Omichinski;

  • 作者单位

    Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Montreal, QC, Canada H2W 1R7 Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada H3C 3J7;

    Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada H3C 3J7;

    Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Montreal, QC, Canada H2W 1R7;

    Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892;

    Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada H3C 3J7;

    Laboratory of Molecular Biochemistry of Hypertension, Clinical Research Institute of Montreal, Montreal, QC, Canada H2W 1R7;

    Department of Biochemistry, Universite de Montreal, Montreal, QC, Canada H3C 3J7;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    NMR; prohormone convertases;

    机译：NMR;原激素转化酶;

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