Structural Mechanisms of Renal Sensory and Transport Proteins
EMSL Project ID
50995
Abstract
The kidneys regulate blood composition, pressure, and volume, balance electrolytes and acid-base, and reabsorb most salts and nutrients from the initial renal filtrate while excreting metabolic wastes, xenobiotics, and toxins into the urine. This fundamental homeostatic role is fulfilled in part by a panoply of renal receptors, pumps, transporters, and ion channels that collectively monitor and respond to the composition, pressure, volume, and flow rates of the blood and urine. We focus on two such important classes of membrane proteins: polycystic kidney disease proteins (PKD1 and PKD2) and cation-chloride cotransporters (CCCs). The PKD1 receptor and PKD2 channel assemble into a heteromeric complex at sensory primary cilia where they detect and respond to as-yet unknown chemical ligand(s) and/or mechanical force, contributing to the establishment and maintenance of the exquisite tubular architecture of nephrons. Mutations in either PKD1 or PKD2 lead to autosomal dominant polycystic kidney disease (ADPKD) characterized by progressive accumulation of cysts, loss of normal renal tissues, and consequently, end stage renal diseases. CCCs consist of three Na+-dependent Na+-(K+)-Cl- (NCC and NKCC1-2) and four Na+-independent K+-Cl? (KCC1-4) cotransporters. In the kidneys, NKCC2 and NCC reabsorb ions from the forming urine, which is fundamental for balancing electrolytes and maintenance of blood pressure. Importantly, NKCC2 and NCC are the molecular targets of the first-line anti-hypertensive loop and thiazide diuretics, respectively. Here, we propose to determine cryo-EM structures of the PKD1/2 complex and CCCs that would provide insights into their assembly, functions, regulation, pharmacology, and roles in human diseases.
Project Details
Start Date
2019-08-01
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Yang X., Q. Wang, and E. Cao. 2020. "Structure of the Human Cation–chloride Cotransporter NKCC1 Determined by Single-particle Electron Cryo-microscopy." Nature Communications 11, no. 1016. doi:10.1038/s41467-020-14790-3
PMID: 32081947 PMCID: PMC7035313 DOI: 10.1038/s41467-020-14790-3