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.

Basic Information of CNNM4
Protein Name Metal transporter CNNM4
Gene Name CNNM4
Aliases Ancient conserved domain-containing protein 4, Cyclin-M4
Organism Homo sapiens (Human)
UniProt ID Q6P4Q7
Transmembrane Times Multi-pass membrane
Length (aa) 775

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.

CNNM4 Membrane Protein IntroductionFig.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 progressionJournal 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

To obtain the soluble and functional target protein, the versatile Magic™ membrane protein production platform in Creative Biolabs enables many flexible options, from which you can always find a better match for your particular project. Aided by our versatile Magic™ anti-membrane protein antibody discovery platform, we also provide customized anti-CNNM4 antibody development services.

As a forward-looking research institute as well as a leading customer service provider in the field of membrane protein, Creative Biolabs has won good reputation among our worldwide customers for successfully accomplishing numerous challenging projects including generation of many functional membrane proteins. Please feel free to contact us for more information.


  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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