Title : Structure of the polycystic kidney disease
TRP channel Polycystin-2 (
PC2 )
Abstract :
- Mutations in either polycystin-1 ( PC1 or PKD1 ) or polycystin-2 ( PC2 , PKD2 or TRPP1 ) cause autosomal-dominant polycystic kidney disease (ADPKD) through unknown mechanisms
- Here we present the structure of human PC2 in a closed conformation, solved by electron cryomicroscopy at 4.2-Å resolution
- The structure reveals a novel polycystin-specific 'tetragonal opening for polycystins' (TOP) domain tightly bound to the top of a classic transient receptor potential ( TRP ) channel structure
- The TOP domain is formed from two extensions to the voltage-sensor-like domain (VSLD); it covers the channel 's endoplasmic reticulum lumen or extracellular surface and encloses an upper vestibule, above the pore filter, without blocking the ion-conduction pathway
- The TOP-domain fold is conserved among the polycystins, including the homologous channel-like region of PC1 , and is the site of a cluster of ADPKD-associated missense variants
- Extensive contacts among the TOP-domain subunits , the pore and the VSLD provide ample scope for regulation through physical and chemical stimuli