title: Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2.
abstract: Phosphatases of regenerating liver (PRLs), the most oncogenic of all protein-tyrosine phosphatases (PTPs), play a critical role in metastatic progression of cancers. Recent findings established a new paradigm by uncovering that their association with magnesium transporters of the cyclin M (CNNM) family causes a rise in intracellular magnesium levels that promote oncogenic transformation. Recently, however, essential roles for regulation of the circadian rhythm and reproduction of the CNNM family have been highlighted. Here, we describe the crystal structure of PRL-1 in complex with the Bateman module of CNNM2 (CNNM2BAT), which consists of two cystathionine β-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disc-like homodimer of CNNM2BATbound to two independent PRL-1 molecules, each one located at opposite tips of the disc. The structure highlights the key role played by Asp-558 at the extended loop of the CBS2 motif of CNNM2 in maintaining the association between the two proteins and proves that the interaction between CNNM2 and PRL-1 occurs via the catalytic domain of the phosphatase. Our data shed new light on the structural basis underlying the interaction between PRL phosphatases and CNNM transporters and provides a hypothesis about the molecular mechanism by which PRL-1, upon binding to CNNM2, might increase the intracellular concentration of Mg2+thereby contributing to tumor progression and metastasis. The availability of this structure sets the basis for the rational design of compounds modulating PRL-1 and CNNM2 activities.
authors.affiliation: From the Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Giménez-Mascarell
authors.affiliation: From the Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Oyenarte
authors.affiliation: the Rosalind and Morris Goodman Cancer Research Centre.
authors.forename: Serge
authors.initials: S
authors.lastname: Hardy
authors.affiliation: the Department of Pediatric Nephrology, Charité Universitäts Medizin, Berlin, 13353 Berlin, Germany.|the Berlin Institute of Health, Berlin, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Breiderhoff
authors.affiliation: the In-Cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Robert-Rössle Strasse 10, 13125 Berlin, Germany.
authors.forename: Marchel
authors.initials: M
authors.lastname: Stuiver
authors.affiliation: the Rosalind and Morris Goodman Cancer Research Centre.|Department of Biochemistry, and.
authors.forename: Elie
authors.initials: E
authors.lastname: Kostantin
authors.affiliation: From the Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: Tammo
authors.initials: T
authors.lastname: Diercks
authors.affiliation: the Department of Physical Chemistry, Faculty of Sciences, University of Granada, Av. Fuentenueva s/n, 18071 Granada, Spain.
authors.forename: Angel L
authors.initials: AL
authors.lastname: Pey
authors.affiliation: From the Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: June
authors.initials: J
authors.lastname: Ereño-Orbea
authors.affiliation: the Metabolomics Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.
authors.forename: María Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: the Department of Biomedical Sciences, An-Najah National University, P. O. Box 7, Nablus, Palestinian Territory, and.
authors.forename: Reham
authors.initials: R
authors.lastname: Khalaf-Nazzal
authors.affiliation: the Research Unit, Nuestra Señora de Candelaria University Hospital, 38010 Santa Cruz de Tenerife, Spain.
authors.forename: Felix
authors.initials: F
authors.lastname: Claverie-Martin
authors.affiliation: the Department of Pediatric Nephrology, Charité Universitäts Medizin, Berlin, 13353 Berlin, Germany, Dominik.Mueller@charite.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.affiliation: the Rosalind and Morris Goodman Cancer Research Centre, Michel.tremblay@mcgill.ca.|Department of Biochemistry, and.|Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: From the Structural Biology Unit, Center for Cooperative Research in Biosciences (CIC bioGUNE), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain, amartinez@cicbiogune.es.
authors.forename: Luis Alfonso
authors.identifier: 0000-0002-5856-9377
authors.initials: LA
authors.lastname: Martínez-Cruz
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; C510868:Cnnm2 protein, mouse; D017874:Immediate-Early Proteins; D015513:Oncogene Proteins; D017027:Protein Tyrosine Phosphatases; C087359:Ptp4a1 protein, mouse; D008274:Magnesium
keywords: PRL-1, CNNM2, CBS domain; cancer; cell proliferation; magnesium; phosphatase; transporter