PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.
Details
Serval ID
serval:BIB_754A6FBF09D8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.
Journal
Molecular biology of the cell
ISSN
1939-4586 (Electronic)
ISSN-L
1059-1524
Publication state
Published
Issued date
01/11/2021
Peer-reviewed
Oui
Editor
Marks Michael
Volume
32
Number
21
Pages
ar34
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Copper homeostasis is crucial for cellular physiology and development, and its dysregulation leads to disease. The Menkes ATPase ATP7A plays a key role in copper efflux, by trafficking from the Golgi to the plasma membrane upon cell exposure to elevated copper, but the mechanisms that target ATP7A to the cell periphery are poorly understood. PDZD11 interacts with the C-terminus of ATP7A, which contains sequences involved in ATP7A trafficking, but the role of PDZD11 in ATP7A localization is unknown. Here we identify PLEKHA5 and PLEKHA6 as new interactors of PDZD11 that bind to the PDZD11 N-terminus through their WW domains similarly to the junctional protein PLEKHA7. Using CRISPR-KO kidney epithelial cells, we show by immunofluorescence microscopy that WW-PLEKHAs (PLEKHA5, PLEKHA6, PLEKHA7) recruit PDZD11 to distinct plasma membrane localizations and that they are required for the efficient anterograde targeting of ATP7A to the cell periphery in elevated copper conditions. Pull-down experiments show that WW-PLEKHAs promote PDZD11 interaction with the C-terminus of ATP7A. However, WW-PLEKHAs and PDZD11 are not necessary for ATP7A Golgi localization in basal copper, ATP7A copper-induced exit from the Golgi, and ATP7A retrograde trafficking to the Golgi. Finally, measuring bioavailable and total cellular copper, metallothionein-1 expression, and cell viability shows that WW-PLEKHAs and PDZD11 are required for maintaining low intracellular copper levels when cells are exposed to elevated copper. These data indicate that WW-PLEKHAs-PDZD11 complexes regulate the localization and function of ATP7A to promote copper extrusion in elevated copper.
Keywords
Adenosine Triphosphatases/metabolism, Biological Transport, Carrier Proteins/genetics, Carrier Proteins/metabolism, Cell Communication, Cell Membrane/metabolism, Copper/metabolism, Copper-Transporting ATPases/metabolism, Cytoplasm/metabolism, Golgi Apparatus/metabolism, Homeostasis, Humans, Intracellular Signaling Peptides and Proteins/genetics, Intracellular Signaling Peptides and Proteins/metabolism, Kidney/cytology, Phagocytosis, Protein Transport
Pubmed
Web of science
Create date
24/01/2024 12:42
Last modification date
18/09/2024 7:08