InterPro domain: IPR045095

Proteins containing the ancient conserved domain protein/cyclin M (CNNM) are integral membrane proteins that are conserved from bacteria to humans. CNNM family members influence metal ion homeostasis through mechanisms that may not involve direct membrane transport of the ions [ 1 , 2 , 3 , 4 ]. Structurally, CNNMs contain large cytosolic regions composed of a CBS-pair and a cyclic nucleotide-binding homology (CNBH) domain [ 5 ]. In mammals, the CNNM family consists of 4 integral membrane proteins (CNNM1-4). NNM-associated Mg2+ transport has been shown shown to be regulated by the binding of phosphatases of regenerating liver (PRLs). PRLs are potent oncogenes with strong association with metastatic cancers [ 6 , 7 ]. In Caenorhabditis elegans, there are five CNNM family members that may work together to regulate Mg2+ homeostasis [ 7 ].

1. Manganese toxicity and Saccharomyces cerevisiae Mam3p, a member of the ACDP (ancient conserved domain protein) family. Biochem. J. 386, 479-87
2. Membrane topology and intracellular processing of cyclin M2 (CNNM2). J. Biol. Chem. 287, 13644-55
3. Phosphocysteine in the PRL-CNNM pathway mediates magnesium homeostasis. EMBO Rep. 17, 1890-1900
4. Structural Basis of the Oncogenic Interaction of Phosphatase PRL-1 with the Magnesium Transporter CNNM2. J. Biol. Chem. 292, 786-801
5. Mg²⁺-ATP Sensing in CNNM, a Putative Magnesium Transporter. Structure 28, 324-335.e4
6. Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). Gene 306, 37-44
7. Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans. PLoS Genet 12, e1006276