title: The Role of G-Protein-Coupled Receptor Proteolysis Site Cleavage of Polycystin-1 in Renal Physiology and Polycystic Kidney Disease.
abstract: Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the larger GAIN domain. Given the considerable biochemical complexity of PC1 molecules generated in vivo by this process, GPS cleavage has several profound implications on the intracellular trafficking and localization in association with their particular function. The critical nature of GPS cleavage is further emphasized by the increasing numbers of PKD1 mutations that significantly affect this cleavage process. The GAIN domain with the GPS motif therefore represents the key structural element with fundamental importance for PC1 and might be polycystic kidney disease's (PKD) Achilles' heel in a large spectrum of PKD1 missense mutations. We highlight the central roles of PC1 cleavage for the regulation of its biogenesis, intracellular trafficking and function, as well as its significance in polycystic kidney disease.
authors.affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montreal, Universite de Montreal, Faculte de Medecine, Montréal, Québec H2W 1R7, Canada. marie.trudel@ircm.qc.ca.
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
authors.affiliation: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. qyao@medicine.umaryland.edu.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. fqian@medicine.umaryland.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
keywords: GAIN domain; GPS motif; adhesion GPCR; cis-autoproteolysis; polycystic kidney disease; polycystin