Institute of Pharmacology and Toxicology, Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine, University of Wrzburg, 97078 Würzburg, Germany.
J Biol Chem. 2010 Mar 19;285(12):8665-74. doi: 10.1074/jbc.M109.058685. Epub 2010 Jan 15.
The receptor for parathyroid hormone (PTHR) is a main regulator of calcium homeostasis and bone maintenance. As a member of class B of G protein-coupled receptors, it harbors a large extracellular domain, which is required for ligand binding. Here, we demonstrate that the PTHR extracellular domain is cleaved by a protease belonging to the family of extracellular metalloproteinases. We show that the cleavage takes place in a region of the extracellular domain that belongs to an unstructured loop connecting the ligand-binding parts and that the N-terminal 10-kDa fragment is connected to the receptor core by a disulfide bond. Cleaved receptor revealed reduced protein stability compared with noncleaved receptor, suggesting degradation of the whole receptor. In the presence of the agonistic peptides PTH(1-34), PTH(1-14), or PTH(1-31), the processing of the PTHR extracellular domain was inhibited, and receptor protein levels were stabilized. A processed form of the PTHR was also detected in human kidney. These findings suggest a new model of PTHR processing and regulation of its stability.
甲状旁腺激素受体（PTHR）是钙稳态和骨骼维持的主要调节剂。作为 G 蛋白偶联受体家族 B 的成员，它具有一个大的细胞外结构域，这是配体结合所必需的。在这里，我们证明 PTHR 细胞外结构域被属于细胞外金属蛋白酶家族的蛋白酶切割。我们表明，切割发生在细胞外结构域的一个区域，该区域属于连接配体结合部分的无规卷曲，并且 N 端 10kDa 片段通过二硫键与受体核心相连。与未切割的受体相比，切割的受体显示出降低的蛋白质稳定性，这表明整个受体的降解。在激动肽 PTH(1-34)、PTH(1-14)或 PTH(1-31)的存在下，PTHR 细胞外结构域的加工被抑制，并且受体蛋白水平被稳定。在人肾脏中也检测到 PTHR 的一种加工形式。这些发现表明了 PTHR 加工和其稳定性调节的新模型。
