Structures and Mechanisms of the Cation Chloride Cotransporters
EMSL Project ID
50678
Abstract
The secondary active cation-chloride cotransporters (CCCs) utilize the Na+ and/or K+ gradients created by the Na+-K+-ATPase to move Cl- into or out of cells. The 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. The CCCs, including NKCC2 and NCC, are regulated by the WNKs-SPAK kinase cascade. Mutations in NKCC2, NCC, or WNKs and their upstream regulators (CUL3/KLHL3; components of an E3 ubiquitin ligase) all lead to salt-wasting hypotensive Gitelman's and Batter's syndromes or hypertensive Gordon's syndrome. Indeed, NKCC2 and NCC are the molecular targets of the first-line anti-hypertensive loop and thiazide diuretics, respectively. One of the major goals of my group at the University of Utah is to determine cryo-EM structures of CCCs to elucidate how they specifically recognize and transport ions, how diuretic drugs interact with and inhibit ion transport, and how phosphorylation allosterically regulates the ion transport pathway. In this proposal, we apply for microscope times to screen samples on a Arctica microscope at PNCC.
Project Details
Start Date
2019-01-14
End Date
2019-05-07
Status
Closed
Released Data Link
Team
Principal Investigator