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J. Biol. Chem., Vol. 282, Issue 30, 21729-21737, July 27, 2007

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Characterization of cis-Autoproteolysis of Polycystin-1, the Product of Human Polycystic Kidney Disease 1 Gene^*

From the Division of Nephrology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

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 HLT³⁰⁴⁹ 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.

Received for publication, April 17, 2007 , and in revised form, May 18, 2007.

^* The work was supported by National Institutes of Health Grant R01DK062199 (to F. Q.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 720 Rutland Ave., Ross Bldg. 954, Baltimore, MD 21205-2196. Fax: 410-614-5129; E-mail: fqjhupkd{at}jhmi.edu.

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