TY  - JOUR
AU  - Giménez-Mascarell, Paula
AU  - Oyenarte, Iker
AU  - Hardy, Serge
AU  - Breiderhoff, Tilman
AU  - Stuiver, Marchel
AU  - Kostantin, Elie
AU  - Diercks, Tammo
AU  - Pey, Angel L
AU  - Ereño-Orbea, June
AU  - Martínez-Chantar, María Luz
AU  - Khalaf-Nazzal, Reham
AU  - Claverie-Martin, Felix
AU  - Müller, Dominik
AU  - Tremblay, Michel L
AU  - Martínez-Cruz, Luis Alfonso
TI  - Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2.
JO  - JBC papers in press
VL  - 292
IS  - 3
SN  - 0021-9258
CY  - Bethesda, MD
PB  - American Soc. for Biochemistry and Molecular Biology
M1  - DZNE-2025-00365
SP  - 786 - 801
PY  - 2017
N1  - ISSN 0021-9258 not unique: **2 hits**.
AB  - 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 CNNM2BAT bound 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.
KW  - Animals
KW  - Cation Transport Proteins: chemistry
KW  - Cation Transport Proteins: genetics
KW  - Cation Transport Proteins: metabolism
KW  - Immediate-Early Proteins: chemistry
KW  - Immediate-Early Proteins: genetics
KW  - Immediate-Early Proteins: metabolism
KW  - Magnesium: chemistry
KW  - Magnesium: metabolism
KW  - Mice
KW  - Neoplasm Metastasis
KW  - Neoplasms: genetics
KW  - Neoplasms: metabolism
KW  - Neoplasms: pathology
KW  - Oncogene Proteins: chemistry
KW  - Oncogene Proteins: genetics
KW  - Oncogene Proteins: metabolism
KW  - Protein Binding
KW  - Protein Domains
KW  - Protein Structure, Secondary
KW  - Protein Tyrosine Phosphatases: chemistry
KW  - Protein Tyrosine Phosphatases: genetics
KW  - Protein Tyrosine Phosphatases: metabolism
KW  - PRL-1, CNNM2, CBS domain (Other)
KW  - cancer (Other)
KW  - cell proliferation (Other)
KW  - magnesium (Other)
KW  - phosphatase (Other)
KW  - transporter (Other)
KW  - Cation Transport Proteins (NLM Chemicals)
KW  - Cnnm2 protein, mouse (NLM Chemicals)
KW  - Immediate-Early Proteins (NLM Chemicals)
KW  - Oncogene Proteins (NLM Chemicals)
KW  - Protein Tyrosine Phosphatases (NLM Chemicals)
KW  - Ptp4a1 protein, mouse (NLM Chemicals)
KW  - Magnesium (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27899452
C2  - pmc:PMC5247653
DO  - DOI:10.1074/jbc.M116.759944
UR  - https://pub.dzne.de/record/276852
ER  -