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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder affecting one in 500–1000 individuals worldwide [1]
ADPKD is characterized by the formation of kidney cysts that gradually replace normal kidney parenchyma [5,6]
The N-terminal extracellular region contains a set of domains involved in protein-protein interactions and the ~1000 aa receptor for egg jelly (REJ) module that harbors four FnIII domains [10,11]
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder affecting one in 500–1000 individuals worldwide [1]. CTT of PC1 can beG-proteins released by γ-secretase-mediated cleavage andvia regulates the CHOP pathway heterotrimeric in vitro [24] and mediate AP activation heterotrimeric. PC2 [28,29,30], γ-secretase-mediated cleavage and regulates the CHOP pathway domain by binding transcription resulting presumably the formation a receptor-channel at the plasma membrane, as well factors. PC1/2 is proposed to mediate signaling pathways in response to mechanical [31], an organelle that is most relevant to the pathogenesis of ADPKD [32,33,34]. A schematic diagram domainorganization organization of various products generated by cleavage at the GPCR site (GPS)site motif within thewithin. B; GPS, receptor site motif; TM, transmembrane domain; transmembrane domain; CTT, C-terminal tail.
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