Chen Yu Seby, Gehring Kalle
Department of Biochemistry & Molecular Biology, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada.
Department of Biochemistry & Centre de Recherche en Biologie Structurale, McGill University, Montreal, QC, Canada.
FEBS J. 2023 Dec;290(23):5475-5495. doi: 10.1111/febs.16872. Epub 2023 Jun 2.
Magnesium (Mg ) is the most abundant divalent cation in cells and plays key roles in almost all biological processes. CBS-pair domain divalent metal cation transport mediators (CNNMs) are a newly characterized class of Mg transporters present throughout biology. Originally discovered in bacteria, there are four CNNM proteins in humans, which are involved in divalent cation transport, genetic diseases, and cancer. Eukaryotic CNNMs are composed of four domains: an extracellular domain, a transmembrane domain, a cystathionine-β-synthase (CBS)-pair domain, and a cyclic nucleotide-binding homology domain. The transmembrane and CBS-pair core are the defining features of CNNM proteins with over 20 000 protein sequences known from over 8000 species. Here, we review the structural and functional studies of eukaryotic and prokaryotic CNNMs that underlie our understanding of their regulation and mechanism of ion transport. Recent structures of prokaryotic CNNMs confirm the transmembrane domain mediates ion transport with the CBS-pair domain likely playing a regulatory role through binding divalent cations. Studies of mammalian CNNMs have identified new binding partners. These advances are driving progress in understanding this deeply conserved and widespread family of ion transporters.
镁（Mg²⁺）是细胞中含量最丰富的二价阳离子，在几乎所有生物过程中都发挥着关键作用。胱硫醚-β-合酶（CBS）结构域二价金属阳离子转运介质（CNNMs）是一类新发现的、广泛存在于生物界的镁转运蛋白。最初在细菌中发现，人类有四种CNNM蛋白，它们参与二价阳离子转运、遗传疾病和癌症。真核生物的CNNM由四个结构域组成：一个细胞外结构域、一个跨膜结构域、一个胱硫醚-β-合酶（CBS）结构域对和一个环核苷酸结合同源结构域。跨膜结构域和CBS结构域对是CNNM蛋白的标志性特征，已知来自8000多个物种的超过20000个蛋白质序列。在这里，我们综述了真核生物和原核生物CNNM的结构和功能研究，这些研究是我们理解其调控和离子转运机制的基础。原核生物CNNM的最新结构证实，跨膜结构域介导离子转运，而CBS结构域对可能通过结合二价阳离子发挥调节作用。对哺乳动物CNNM的研究已经确定了新的结合伙伴。这些进展正在推动我们对这个高度保守且广泛存在的离子转运蛋白家族的理解取得进展。
