6dj3
Crystal structure of CNNM2 cyclic nucleotide-binding homology domain
Structural highlights
DiseaseCNNM2_HUMAN Familial primary hypomagnesemia with normocalcuria and normocalcemia. The disease is caused by mutations affecting the gene represented in this entry. FunctionCNNM2_HUMAN Divalent metal cation transporter. Mediates transport of divalent metal cations in an order of Mg(2+) > Co(2+) > Mn(2+) > Sr(2+) > Ba(2+) > Cu(2+) > Fe(2+) (By similarity). Publication Abstract from PubMedProteins of the family of CBS domain divalent metal cation transport mediators (CNNMs, also called ancient conserved domain proteins, ACDPs) are represented by four integral membrane proteins that have been proposed to function as Mg(2+) transporters. CNNMs are associated with a number of genetic diseases affecting ion movement and cancer via their association with highly oncogenic phosphatases of regenerating liver (PRL). Structurally, CNNMs contain an N-terminal extracellular domain, a transmembrane domain (DUF21), and a large cytosolic region containing a cystathionine-beta-synthase (CBS) domain and a putative cyclic nucleotide-binding homology (CNBH) domain. Although the CBS domain has been extensively characterized, little is known about the CNBH domain. Here, we determined the first crystal structures of the CNBH domains of CNNM2 and CNNM3 at 2.6 and 1.9 A resolutions. Contrary to expectation, these domains did not bind cyclic nucleotides, but mediated dimerization both in crystals and in solution. Analytical ultracentrifugation experiments revealed an inverse correlation between the propensity of the CNBH domains to dimerize and the ability of CNNMs to mediate Mg(2+) efflux. CNBH domains from active family members were observed as both dimers and monomers, whereas the inactive member, CNNM3, was observed only as a dimer. Mutational analysis revealed that the CNBH domain was required for Mg(2+) efflux activity of CNNM4. This work provides a structural basis for understanding the function of CNNM proteins in Mg(2+) transport and associated diseases. The cyclic nucleotide-binding homology domain of the integral membrane protein CNNM mediates dimerization and is required for Mg(2+) efflux activity.,Chen YS, Kozlov G, Fakih R, Funato Y, Miki H, Gehring K J Biol Chem. 2018 Oct 19. pii: RA118.005672. doi: 10.1074/jbc.RA118.005672. PMID:30341174[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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