6g52 | pdb_00006g52
CRYSTAL STRUCTURE OF THE CNMP BINDING DOMAIN OF THE MAGNESIUM TRANSPORTER CNNM4
Structural highlights
Disease[CNNM4_HUMAN] Jalili syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function[CNNM4_HUMAN] Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions (By similarity). May play a role in biomineralization and retinal function.[1] [2] Publication Abstract from PubMedThe 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 Mg(2+)-efflux capacity, thus resulting in an increased intracellular Mg(2+) 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 Mg(2+), 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 Mg(2+) induced sliding of the inserting CBS1 motives of the Bateman module, from a twisted to a flat disk shaped dimer. Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4.,Gimenez-Mascarell P, Oyenarte I, Gonzalez-Recio I, Fernandez-Rodriguez C, Corral-Rodriguez MA, Campos-Zarraga I, Simon J, Kostantin E, Hardy S, Diaz Quintana A, Zubillaga Lizeaga M, Merino N, Diercks T, Blanco FJ, Diaz Moreno I, Martinez-Chantar ML, Tremblay ML, Muller D, Siliqi D, Martinez-Cruz LA Int J Mol Sci. 2019 Dec 12;20(24). pii: ijms20246279. doi: 10.3390/ijms20246279. PMID:31842432[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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