CNNM4 Membrane Protein Introduction

Introduction of CNNM4

CNNM4 belongs to the Ancient conserved domain protein/cyclin M (CNNM) family which contains 4 integral membrane proteins. All of them possess an evolutionarily conserved domain’ (ACD) that is present in many species from bacteria to zebrafish to man. CNNM4 is encoded by the CNNM4 gene which is located at 2p12-p11.2. The molecular weight is 86,607 Da. Functionally, CNNM4 is predicted to owns magnesium ion transmembrane transporter activity and sodium ion transmembrane transporter activity.

Function of CNNM4 Membrane Protein

CNNM4 is widely expressed, especially in heart. At the same time, CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. It has been proven that CNNM4 mediates transcellular Mg²⁺ transport across the intestinal epithelia. CNNM4 can extrude Mg²⁺ by exchanging intracellular Mg²⁺ with extracellular Na⁺. In term of structure, CNNM4 is a multidomain protein formed of a DUF21 domain (residues 184–358), a cyclin-box motif (residues 548–578), a cyclic nucleotide monophosphate (cNMP)-binding domain (residues 575–695) and two consecutive cystathionine β-synthase (CBS) domains (residues 377–438 and 445–511. Moreover, CNNM4 can bind phosphatase of regenerating liver (PRL), which is frequently overexpressed in malignant human cancers, and some studies have proven that there is an inverse relationship between colon cancer malignancy and CNNM4 expression, and CNNM4-dependent Mg²⁺ efflux suppresses tumor progression by regulating energy metabolism.

Fig.1 Domain distribution in the human CNNM4 metal transporter. (García, 2011)

Application of CNNM4 Membrane Protein in Literature

1. Yamazaki D., et al. The Mg²⁺ transporter CNNM4 regulates sperm Ca²⁺ homeostasis and it is essential for reproduction. Journal of Cell Science. 2016, 129(9):1940. PubMed ID: 27006114
   
   

   This article reports that CNNM4 is required for Ca²⁺ influx during capacitation. Ca²⁺ influx is perturbed in CNNM4-deficient sperm and forced Ca²⁺ entry into the sperm will normalize the level of tyrosine phosphorylation.

2. Funato Y., et al. Membrane protein CNNM4-dependent Mg²⁺ efflux suppresses tumor progression. Journal of Clinical Investigation. 2014, 124(12):5398-5410. PubMed ID: 25347473
   
   

   This article reveals that tumor progression can be suppressed by CNNM4-dependent Mg²⁺ efflux through regulating energy metabolism. The article determined that CNNM4 stimulates Mg²⁺ efflux and binds phosphatase of regenerating liver (PRL) which is usually overexpressed in malignant human cancers.

3. García I.G., et al. Purification, crystallization and preliminary crystallographic analysis of the CBS pair of the human metal transporter CNNM4. Acta Crystallographica, 2011, 67(3):349-353. PubMed ID: 21393841
   
   

   Authors in this group mainly describe the purification and preliminary crystallographic analysis of the CBS-pair regulatory domain of ACDP4 (the human ancient domain protein 4), also known as CNNM4.

4. Yamazaki D., et al. Basolateral Mg²⁺ Extrusion via CNNM4 Mediates Transcellular Mg²⁺ Transport across Epithelia: A Mouse Model. Plos Genetics. 2013, 9(12): e1003983. PubMed ID: 24339795
   
   

   Authors in this article take advantage of a mouse model to study the crucial importance of Mg²⁺ extrusion by CNNM4 in organismal and topical regulation of magnesium.

5. Hirata Y., et al. Basolateral sorting of the Mg (²⁺) transporter CNNM4 requires interaction with AP-1A and AP-1B. Biochemical & Biophysical Research Communications. 2014, 455(3-4):184-189. PubMed ID: 25449265
   
   

   This article shows the complementary importance of clathrin adaptor protein (AP) complexes AP-1A and AP-1B in basolateral sorting of CNNM4. The results imply that CNNM4 is sorted to the basolateral membrane by the complementary function of AP-1A and AP-1B.

CNNM4 Preparation Options

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Reference

1. García I. G., et al. (2011). Purification, crystallization and preliminary crystallographic analysis of the CBS pair of the human metal transporter cnnm4. Acta Crystallographica. 67(3), 349-353.

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