Dataset Information

Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

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 Mg2+ 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 Mg2+ levels. Phosphorylation blocks PRL binding to CNNM Mg2+ transporters, and mutations that block the PRL-CNNM interaction prevent regulation of Mg2+ efflux in cultured cells. The crystal structure of the complex of PRL2 and the CBS-pair domain of the Mg2+ 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.

SUBMITTER: Gulerez I

PROVIDER: S-EPMC5283600 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

Gulerez Irina I Funato Yosuke Y Wu Howie H Yang Meng M Kozlov Guennadi G Miki Hiroaki H Gehring Kalle K

EMBO reports 20161117 12

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<sup>2+</sup> transport, which is important for energy metabolism and tumor progression. Here, we report that PRL-CNNM complex ...[more]

PMID: 27856537

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Project description:Magnesium (Mg2+) is indispensable for several vital functions, such as neurotransmission, cardiac conductance, blood glucose, blood pressure regulation, and proper function of more than 300 enzymes. Thus, Mg2+ homeostasis is subject to tight regulation. Besides the fast and immediate regulation of plasma Mg2+, a major part of Mg2+ homeostasis is realized by a concerted action of epithelial molecular structures that tightly control intestinal uptake and renal absorption. This mechanism is provided by a combination of para- and transcellular pathways. Whereas the first pathway provides the organism with a maximal amount of vital substances by a minimal energy expenditure, the latter enables controlling and fine-tuning by means of local and regional regulatory systems and also, hormonal control. The paracellular pathway is driven by an electrochemical gradient and realized in principal by the tight junction (TJ), a supramolecular organization of membrane-bound proteins and their adaptor and scaffolding proteins. TJ determinants are claudins (CLDN), a family of membrane spanning proteins that generate a barrier or a pore between two adjacent epithelial cells. Many insights into molecular mechanisms of Mg2+ handling have been achieved by the identification of alterations and mutations in human genes which cause disorders of paracellular Mg2+ pathways (CLDN10, CLDN14, CLDN16, CLDN19). Also, in the distal convoluted tubule, a basolateral protein, CNNM2, causes if mutated, familial dominant and also recessive renal Mg2+ wasting, albeit its true function has not been clarified yet, but is assumed to play a key role in the transcellular pathway. Moreover, mutations in human genes that are involved in regulating these proteins directly or indirectly cause, if mutated human diseases, mostly in combination with comorbidities as diabetes, cystic renal disease, or metabolic abnormalities. Generation and characterization of animal models harboring the corresponding mutations have further contributed to the elucidation of physiology and pathophysiology of Mg2+ disorders. Finally, high-end crystallization techniques allow understanding of Mg2+ handling in more detail. As this field is rapidly growing, we describe here the principles of physiology and pathophysiology of epithelial transport of renal Mg2+ homeostasis with emphasis on recently identified mechanisms involved.

Dataset Information

Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

Publications

Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis.

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