5K22

Crystal structure of the complex between human PRL-2 phosphatase in reduced state and Bateman domain of human CNNM3

Summary for 5K22

• Entry DOI: 10.2210/pdb5k22/pdb
• Related: 5K23 5K24 5K25
• Descriptor: Protein tyrosine phosphatase type IVA 2, Metal transporter CNNM3 (3 entities in total)
• Functional Keywords: alpha-beta fold, complex, protein binding, phosphatase, transport protein-protein binding complex, transport protein/protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 38430.89

Authors

Kozlov, G.,Wu, H.,Gehring, K. (deposition date: 2016-05-18, release date: 2016-10-12, Last modification date: 2024-03-06)

Primary citation

Gulerez, I.,Funato, Y.,Wu, H.,Yang, M.,Kozlov, G.,Miki, H.,Gehring, K.
Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.
EMBO Rep., 17:1890-1900, 2016

PubMed Abstract: PRLs (phosphatases of regenerating liver) are frequently overexpressed in human cancers and are prognostic markers of poor survival. Despite their potential as therapeutic targets, their mechanism of action is not understood in part due to their weak enzymatic activity. Previous studies revealed that PRLs interact with CNNM ion transporters and prevent CNNM4-dependent Mg transport, which is important for energy metabolism and tumor progression. Here, we report that PRL-CNNM complex formation is regulated by the formation of phosphocysteine. We show that cysteine in the PRL catalytic site is endogenously phosphorylated as part of the catalytic cycle and that phosphocysteine levels change in response to Mg levels. Phosphorylation blocks PRL binding to CNNM Mg transporters, and mutations that block the PRL-CNNM interaction prevent regulation of Mg efflux in cultured cells. The crystal structure of the complex of PRL2 and the CBS-pair domain of the Mg transporter CNNM3 reveals the molecular basis for the interaction. The identification of phosphocysteine as a regulatory modification opens new perspectives for signaling by protein phosphatases.

PubMed: 27856537
DOI: 10.15252/embr.201643393

Experimental method

X-RAY DIFFRACTION (3 Å)