期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 24, 页码 -出版社
MDPI
DOI: 10.3390/ijms20246279
关键词
CNNM4; magnesium; transporter; CNBHD; CBS domain
资金
- Departamento de Educacion, Universidades e Investigacion del Gobierno Vasco [PI2010-17]
- Departamento de Industria, Innovacion, Comercio y Turismo del Gobierno Vasco [ETORTEK IE05-147, IE07-202]
- Diputacion Foral de Bizkaia [7/13/08/2006/11, 7/13/08/2005/14]
- Ministerio Espanol de Ciencia e Innovacion (MICINN) [BFU2010-17857]
- Spanish Ministry of Economy and Competitiveness [PGC2018-096049-B100]
- MICINN CONSOLIDER-INGENIO 2010 Program [CSD2008-00005, 2019073624]
- ALBA Synchrotron
- Diamond Light Source - Gobierno Vasco-Departamento de Salud [2013111114]
- MINECO [SEV-2016-0644, 12.01.134/2bT4]
- Plan Estatal de Investigacion Cientifica y Tecnica y Innovacion - Fondos FEDER, BIOEF (Basque Foundation for Innovation and Health Research) [BIO15/CA/014]
- La CAIXA Foundation and Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica
- Ciberehd_ISCIII_MINECO - Instituto de Salud Carlos III
- Berlin Institute of Health
- Canadian Institute for Health Research [343439, MX15832-9, MX15832-10]
- Ramon Areces Foundation
- Biomolecular Interaction Platform (cicCartuja, Seville) - MINECO [CTQ2017-83810-R]
The four member family of Cyclin and Cystathionine beta-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.
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