Wei Wen, Hackmann Karl, Xu Hangxue, Germino Gregory, Qian Feng
Division of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
J Biol Chem. 2007 Jul 27;282(30):21729-37. doi: 10.1074/jbc.M703218200. Epub 2007 May 24.
Polycystin-1 (PC1), the PKD1 gene product, plays a critical role in renal tubule diameter control and disruption of its function causes cyst formation in human autosomal dominant polycystic kidney disease. Recent evidence shows that PC1 undergoes cleavage at the juxtamembrane G protein-coupled receptor proteolytic site (GPS), a process likely to be essential for its biological activity. Here we further characterized the proteolytic cleavage of PC1 at the GPS domain. We determined the actual cleavage site to be between leucine and threonine of the tripeptide HLT(3049) of human PC1. Cleavage occurs in the early intracellular secretory pathway and requires initial N-glycan attachment but not its subsequent trimming. We provide evidence that the cleavage occurs via a cis-autoproteolytic mechanism involving an ester intermediate as shown for Ntn hydrolases and EMR2.
多囊蛋白-1（PC1）是PKD1基因的产物，在肾小管直径控制中起关键作用，其功能破坏会导致人类常染色体显性多囊肾病中的囊肿形成。最近的证据表明，PC1在近膜G蛋白偶联受体蛋白水解位点（GPS）处发生裂解，这一过程可能对其生物学活性至关重要。在此，我们进一步对PC1在GPS结构域的蛋白水解裂解进行了表征。我们确定实际裂解位点位于人PC1三肽HLT（3049）的亮氨酸和苏氨酸之间。裂解发生在早期细胞内分泌途径中，需要初始N-聚糖附着，但不需要其后续修剪。我们提供的证据表明，裂解是通过一种顺式自蛋白水解机制发生的，该机制涉及酯中间体，如Ntn水解酶和EMR2所示。
