Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2

被引：46

作者：

Gimenez-Mascarell, Paula ^{[1
]}

Oyenarte, Iker ^{[1
]}

Hardy, Serge ^{[2
]}

Breiderhoff, Tilman ^{[5
,6
]}

Stuiver, Marchel ^{[7
]}

Kostantin, Elie ^{[2
,3
]}

Diercks, Tammo ^{[1
]}

Pey, Angel L. ^{[8
]}

Ereno-Orbea, June ^{[1
]}

Luz Martinez-Chantar, Maria ^{[9
]}

Khalaf-Nazzal, Reham ^{[10
]}

Claverie-Martin, Felix ^{[11
]}

Mueller, Dominik ^{[5
]}

Tremblay, Michel L. ^{[2
,3
,4
]}

Alfonso Martinez-Cruz, Luis ^{[1
]}

机构：

[1] Ctr Cooperat Res Biosci CIC bioGUNE, Struct Biol Unit, Technol Pk Bizkaia, Derio 48160, Bizkaia, Spain

[2] McGill Univ, Rosalind & Morris Goodman Canc Res Ctr, Montreal, PQ H3A 1A3, Canada

[3] McGill Univ, Dept Biochem, Montreal, PQ H3A 1A3, Canada

[4] McGill Univ, Dept Med, Div Expt Med, Montreal, PQ H3A 1A3, Canada

[5] Charite, Dept Pediat Nephrol, D-13353 Berlin, Germany

[6] Berlin Inst Hlth, Berlin, Germany

[7] Leibniz Inst Mol Pharmacol FMP Berlin, Dept NMR Supported Struct Biol, In Cell NMR Lab, Robert Rossle Str 10, D-13125 Berlin, Germany

[8] Univ Granada, Fac Sci, Dept Phys Chem, Av Fuentenueva S-N, E-18071 Granada, Spain

[9] Ctr Cooperat Res Biosci CIC bioGUNE, Metabol Unit, Technol Pk Bizkaia, Derio 48160, Bizkaia, Spain

[10] An Najah Natl Univ, Dept Biomed Sci, POB 7, Nablus, Palestine

[11] Nuestra Senora de Candelaria Univ Hosp, Res Unit, Santa Cruz De Tenerife 38010, Spain

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2017年 / 292卷 / 03期

关键词：

PROTEIN-TYROSINE-PHOSPHATASE; CYSTATHIONINE-BETA-SYNTHASE; CONE-ROD DYSTROPHY; CELL-GROWTH; CBS DOMAINS; CANCER; EXPRESSION; MUTATIONS; INVASION; TARGET;

D O I：

10.1074/jbc.M116.759944

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 cyclinM(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 beta-synthase (CBS) domains (IPR000664) and represents an intracellular regulatory module of the transporter. The structure reveals a heterotetrameric association, consisting of a disclike homodimer of CNNM2(BAT) 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 andCNNM2activities.

引用

页码：786 / 801

页数：16