CNNM3 Membrane Protein Introduction

Introduction of CNNM3

CNNM3 belongs to the CNNM family which consists of four members, CNNM1-4 (also referred to as ACDP1–4, ancient conserved domain protein), and all of them is related to magnesium homeostasis of cell. CNNM3 is encoded by the CNNM3 gene, which is located at 2p12-p11.2 and contains 3113 bp of cDNA sequence and encodes a putative protein of 707 AA in human. The molecular weight of CNNM3 is 70,632 Da. CNNM3 is widely expressed in all tissues, but it is expressed at higher level in heart and spleen.

Basic Information of CNNM3
Protein Name	Metal transporter CNNM3
Gene Name	CNNM3
Aliases	Ancient conserved domain-containing protein 3, Cyclin-M3
Organism	Homo sapiens (Human)
UniProt ID	Q8NE01
Transmembrane Times	Multi-pass membrane
Length (aa)	707
Sequence	MAAAVAAAGRLGWLFAALCLGNAAGEAAPGPRVLGFCLEEDGAAGAGWVRGGAARDTPDATFLLRLFGPGFANSSWSWVAPEGAGCREEAASPAGEWRALLRLRLRAEAVRPHSALLAVRVEPGGGAAEEAAPPWALGLGAAGLLALAALARGLQLSALALAPAEVQVLRESGSEAERAAARRLEPARRWAGCALGALLLLASLAQAALAVLLYRAAGQRAVPAVLGSAGLVFLVGEVVPAAVSGRWTLALAPRALGLSRLAVLLTLPVALPVGQLLELAARPGRLRERVLELARGGGDPYSDLSKGVLRCRTVEDVLTPLEDCFMLDASTVLDFGVLASIMQSGHTRIPVYEEERSNIVDMLYLKDLAFVDPEDCTPLSTITRFYNHPLHFVFNDTKLDAVLEEFKRGKSHLAIVQKVNNEGEGDPFYEVLGLVTLEDVIEEIIRSEILDESEDYRDTVVKRKPASLMAPLKRKEEFSLFKVSDDEYKVTISPQLLLATQRFLSREVDVFSPLRISEKVLLHLLKHPSVNQEVRFDESNRLATHHYLYQRSQPVDYFILILQGRVEVEIGKEGLKFENGAFTYYGVSALTVPSSVHQSPVSSLQPIRHDLQPDPGDGTHSSAYCPDYTVRALSDLQLIKVTRLQYLNALLATRAQNLPQSPENTDLQVIPGSQTRLLGEKTTTAAGSSHSRPGVPVEGSPGRNPGV

Function of CNNM3 Membrane Protein

CNNM3 plays an important role in ion transport, especially in the magnesium homeostasis, and it is referred to as a magnesium transporter. It has been showed that CNNM3 forms a functional heterodimer with PRL-2 (phosphatases of regenerating liver-2) of which overexpression in breast cancer cells has been shown to promote tumor growth and to regulate intracellular magnesium levels. Furthermore, secondary structure analysis for the CNNMs reveals the presence of three transmembrane domains located at the N-terminal region, and a C terminus containing a cystathionine beta synthase (CBS) pair domain. In fact, CNNM3 is not a phosphorylated substrate of PRL-2, and the interaction occurs through a loop unique to the CBS pair domains of CNNM3 which exists only in organisms with PRL orthologs. And inhibition of the PRL-2/CNNM3 protein complex formation can decrease breast cancer proliferation and tumor growth. Beyond that, CNNM3 specific single nucleotide polymorphisms are associated with serum magnesium concentrations.

CNNM3 Membrane Protein Introduction Fig.1 Mechanism for the regulation of magnesium transport by the PRL-2/CNNM3 complex (Hardy, 2014).

Application of CNNM3 Membrane Protein in Literature

Zhang H., et al. PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3. Scientific Reports. 2017, 7(1):48. PubMed ID: 28246390

This article suggests a strong association between CNNM3 binding and phosphatase activity. Authors support the contention that PRL acts as pseudo phosphatases which are regulated by chemical modifications of their catalytic cysteine.
Kostantin E., et al. Inhibition of the PRL-2/CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth. Journal of Biological Chemistry. 2016, 291(20):10716-10725. PubMed ID: 26969161

This article shows that the PRL-2/CNNM3 protein complex is related to breast cancer proliferation and tumor growth. This fundamental regulatory function of PRL-2 could potentially lead to broadly applicable and innovative therapeutic avenues in cancer cell.
Hardy S., et al. The protein tyrosine phosphatase PRL-2 interacts with the magnesium transporter CNNM3 to promote oncogenesis. Oncogene. 2014, 34(8):986. PubMed ID: 24632616

Authors in this group reveal that oncogenic PRL-2 controls tumor growth by modulating intracellular magnesium levels through binding with the CNNM3 magnesium transporter.
Wang C.Y., et al. Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). Gene. 2003, 306(6):37. PubMed ID: 12657465

Authors in this article clone four novel human genes that encode the ancient conserved domain proteins. One of them is CNNM3. They also reveal some characterization of the CNNM genes and their encoded protein products.

CNNM3 Preparation Options

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Reference

Hardy S, et al. (2014). The protein tyrosine phosphatase prl-2 interacts with the magnesium transporter cnnm3 to promote oncogenesis. Oncogene. 34(8), 986.

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