CNNM2 Membrane Protein Introduction

Introduction of CNNM2

CNNM2, also named Ancient Conserved Domain Protein 2 (ACDP2), belongs to the CNNM family consisting of four proteins (CNNM1-4) which share homology to cyclins, though no cyclin-related function has been reported until now. CNNM2 is encoded by the CNNM2 gene which is located at 10q24.32, and the monocular weight of CNNM2 is 96,623 Da. The transcript for CNNM2 has 4058 bp of cDNA sequence, encoding a protein of 875 AA. At the same time, CNNM2 is widely conserved among species.

Function of CNNM2 Membrane Protein

CNNM2 is ubiquitously expressed in mammalian tissues, most prominently in kidney, brain, and lung. In the kidney, CNNM2 is mainly expressed along the basolateral membrane of distal tubular segments involved in Mg²⁺ reabsorption. CNNM2 is intensively processed before being expressed in its final structure at the plasma membrane. Genome wide association studies have suggested that CNNM2 is related to coronary artery disease, blood pressure, and schizophrenia, suggesting an important function of CNNM2 in the cardiovascular system and brain. Beyond that, CNNM2 can interact selectively and non-covalently with ATP, and it also owns magnesium ion transmembrane transporter activity. In term of structure, CNNM2 consists of an intracellular C-terminus containing CBS domains and extracellular N-terminus, which are affected by the identified mutations. In addition, CNNM2 is predicted to have four to five transmembrane domains and an extracellular C terminus, and a glycine-rich region (201 – 222, GAGGSGSTGGAVGGKGGSGVAG).

Fig.1 Schematical model of CNNM2 structure (de Baaij, 2012).

Application of CNNM2 Membrane Protein in Literature

1. Guan F., et al. Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population. Schizophrenia Research. 2016, 176(2-3):125-130. PubMed ID: 27401531
   
   

   This article suggests that AS3MT, CNNM2, and CALHM1 are involved with the etiology and pathogenesis of schizophrenia, revealing that these genes are potential targets of interest for the improvement of disease management and the development of novel pharmacological strategies.

2. Sponder G., et al. Human CNNM2 is not a Mg²⁺ transporter per se. Pflugers Arch - Eur J Physiol. 2016, 468: 1223. PubMed ID: 27068403
   
   

   This article primarily reports that CNNM2 is identified as Mg²⁺ homeostatic factor without being a Mg²⁺ transporter per se. They find that sensitivity of CNNM2 expression to extracellular Mg²⁺ depletion depends on cell type.

3. Stuiver M., et al. CNNM2, encoding a basolateral protein required for renal Mg²⁺ handling, is mutated in dominant hypomagnesemia. American Journal of Human Genetics. 2011, 88(3):333-343. PubMed ID: 21397062
   
   

   Data from this article supports the findings of a recent study showing the CNNM2 locus to be associated with serum Mg2þ concentrations.

4. Corralrodríguez M.Á., et al. Nucleotide binding triggers a conformational change of the CBS module of the magnesium transporter CNNM2 from a twisted towards a flat structure. Biochemical Journal. 2014, 464(1):23-34. PubMed ID: 25184538
   
   

   This article suggests that the T568I mutation exerts its pathogenic effect in humans by constraining the conformational equilibrium of the CBS module of CNNM2, which becomes ‘locked’ in its flat form.

5. Arjona F.J., et al. CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genetics. 2014, 10(4): e1004267. PubMed ID: 24699222
   
   

   This article reveals that CNNM2 is fundamental for brain development, neurological functioning, and Mg²⁺ homeostasis. It provides a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype by establishing the loss-of-function zebrafish model for CNNM2 genetic disease.

CNNM2 Preparation Options

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Reference

1. de Baaij J. H., et al. (2012). Membrane topology and intracellular processing of cyclin m2 (cnnm2). Journal of Biological Chemistry. 287(17), 13644-55.

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