Structural insights into the intracellular region of the human magnesium transport mediator CNNM4

DOI: 10.3390/ijms20246279

Authors: Paula Gimenez Mascarell (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Iker Oyenarte (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Irene Gonzalez Recio (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Carmen Fernandez-Rodriguez (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , María Ángeles Corral-Rodríguez (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Igone Campos-Zarraga (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Jorge Simón (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Elie Kostantin (McGill University) , Serge Hardy (McGill University) , Antonio Diaz Quintana (Universidad de Sevilla—CSIC) , Mara Zubillaga Lizeaga (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Nekane Merino (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Tammo Diercks (Center for Cooperative Research in Biosciences (CIC bioGUNE)) , Francisco J. Blanco (Center for Cooperative Research in Biosciences (CIC bioGUNE); IKERBASQUE, Basque Foundation for Science) , Irene Diaz Moreno (Universidad de Sevilla—CSIC) , María Luz Martínez-Chantar (Center for Cooperative Research in Biosciences (CIC bioGUNE); Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)) , Michel L. Tremblay (McGill University) , Dominik Müller (Charité Universitäts medizin) , Dritan Siliqi (Istituto di Cristallografia, Consiglio Nazionale delle Ricerche (CNR)) , Luis Alfonso Martinez-Cruz (Center for Cooperative Research in Biosciences (CIC bioGUNE))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: International Journal Of Molecular Sciences , VOL 20

State: Published (Approved)
Published: December 2019
Diamond Proposal Number(s): 15832

Abstract: The four member family of “Cyclin and Cystathionine β-synthase (CBS) domain divalent metal cation transport mediators”, CNNMs, are the least-studied mammalian magnesium transport mediators. CNNM4 is abundant in the brain and the intestinal tract, and its abnormal activity causes Jalili Syndrome. Recent findings show that suppression of CNNM4 in mice promotes malignant progression of intestinal polyps and is linked to infertility. The association of CNNM4 with phosphatases of the regenerating liver, PRLs, abrogates its Mg2+-efflux capacity, thus resulting in an increased intracellular Mg2+ concentration that favors tumor growth. Here we present the crystal structures of the two independent intracellular domains of human CNNM4, i.e., the Bateman module and the cyclic nucleotide binding-like domain (cNMP). We also derive a model structure for the full intracellular region in the absence and presence of MgATP and the oncogenic interacting partner, PRL-1. We find that only the Bateman module interacts with ATP and Mg2+, at non-overlapping sites facilitating their positive cooperativity. Furthermore, both domains dimerize autonomously, where the cNMP domain dimer forms a rigid cleft to restrict the Mg2+ induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer.

Journal Keywords: CNNM4; magnesium; transporter; CNBHD; CBS domain

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ALBA

Added On: 17/12/2019 11:59

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)