Structural basis for the modulation of MRP2 activity by phosphorylation and drugs.
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Embargo End Date
ICR Authors
Authors
Mazza, T
Roumeliotis, TI
Garitta, E
Drew, D
Rashid, ST
Indiveri, C
Choudhary, JS
Linton, KJ
Beis, K
Roumeliotis, TI
Garitta, E
Drew, D
Rashid, ST
Indiveri, C
Choudhary, JS
Linton, KJ
Beis, K
Document Type
Journal Article
Date
2024-03-04
Date Accepted
2024-02-26
Abstract
Multidrug resistance-associated protein 2 (MRP2/ABCC2) is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. MRP2 dysfunction, in Dubin-Johnson syndrome or by off-target inhibition, for example by the uricosuric drug probenecid, elevates circulating bilirubin glucuronide and is a cause of jaundice. Here, we determine the cryo-EM structure of rat Mrp2 (rMrp2) in an autoinhibited state and in complex with probenecid. The autoinhibited state exhibits an unusual conformation for this class of transporter in which the regulatory domain is folded within the transmembrane domain cavity. In vitro phosphorylation, mass spectrometry and transport assays show that phosphorylation of the regulatory domain relieves this autoinhibition and enhances rMrp2 transport activity. The in vitro data is confirmed in human hepatocyte-like cells, in which inhibition of endogenous kinases also reduces human MRP2 transport activity. The drug-bound state reveals two probenecid binding sites that suggest a dynamic interplay with autoinhibition. Mapping of the Dubin-Johnson mutations onto the rodent structure indicates that many may interfere with the transition between conformational states.
Citation
Nature Communications, 2024, 15 (1), pp. 1983 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723
Collections
Research Team
Functional Proteomics
Prote & Metabolomics Fac
Prote & Metabolomics Fac