Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, is a protein that in humans is encoded by the SLC39A9 gene. This protein is the ninth member out of 14 ZIP family proteins, and is a membrane androgen receptor (mAR) coupled to G proteins that is classified as a zinc transporter protein. ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane.
Classification and nomenclature Mammalian cells have two major groups of zinc transporter proteins; the ones that export zinc from the cytoplasm to the extracellular space (efflux), which are called ZnT (SLC30 family), and ZIP (SLC39 family) proteins whose functions are in the opposite direction (influx). ZIP family proteins are named as Zrt- and Irt-like proteins because of their similarities to Zrt and Irt proteins which are respectively zinc and iron -regulated transporter proteins in yeast and Arabidopsis that were discovered earlier than ZIP and ZnT proteins. ZIP family consists of four subfamilies (I, II, LIV-1, and gufA), and ZIP9 is the only member of subfamily I.
Isoforms ZIP9 can be present as three different isoforms in human cells. The canonical isoform of this protein has a length of 307 amino acids, with a molecular mass of 32251 Da. In the second isoform, amino acids 135–157 are missing, so its length and molecular weight are respectively reduced to 284 amino acids and 29931 Da. In the third isoform the amino acids 233–307 are missing, so the isoform only has 232 amino acids and its molecular mass is 24626 Da. Additionally, the last amino acid of isoform 3, which is usually serine, is replaced with aspartic acid.
Discovery ZIP9 membrane androgen receptor was first discovered in Atlantic croaker (Micropogonias undulatus) brain, ovary and testicular tissues and named "AR2" in 1999, together with another androgen receptor which was found only in brain tissue, and it was named "AR1" in that time. AR1 and AR2 were first thought to be nuclear androgen receptors (nAR), however, further studies on their biochemical and functional features in 2003 illustrated that they were involved in non-genomic mechanisms in the plasma membrane of the cells and were membrane androgen receptors. In 2005, the similarities between the nucleotide and amino acid sequences of AR2 and ZIP family proteins were discovered in other vertebrates, suggesting that AR2 is from this family of proteins. A study in 2014 utilised the latest research technologies to clone and express a particular cDNA of the female Atlantic croaker ovaries, which encoded a protein showing the characteristics of the canonical isoform of ZIP9, as a novel membrane androgen receptor(mAR).
Structure Unlike other ZIP subfamilies that are consisted of 8 transmembrane (TM) domains with an extracellular C-terminal, ZIP9 consists of a 7 TM structure with an intracellular C-terminus. ZIP9 is shorter than other ZIP proteins, and only has about 307 amino acids within its structure, however, like other ZIP proteins, between its domains III and IV, within the intracellular loop, it contains histidine-rich clusters. ZIP9 and other ZIP proteins have polar or charged amino acids in their TM domains which probably play important roles in making ion transfer channels and therefore in importing zinc ions into cytoplasm.
Location, expression and function
ZIP9 influxes zinc ions into the cytosol and its gene is expressed almost in every tissue of human body. The sub-cellular location of ZIP9 is in plasma, nucleus, endoplasmic reticulum and mitochondrial membrane. One of the responsibilities of ZIP9 is the homeostasis of zinc in the secretory pathway, during which this protein stays within the Trans Golgi Network regardless of the change in the concentrations of zinc. ZIP9 is the only ZIP protein that signals through G protein binding, and pharmaceutical agents decrease its ligand binding once ZIP9 is uncoupled from G proteins. ZIP9 is also the only member of ZIP family with mAR characteristics.
Ligands Testosterone has high affinity for ZIP9 with a Kd of 14 nM and acts as an agonist of the receptor. In contrast, the other endogenous androgens dihydrotestosterone (DHT) and androstenedione show low affinity for the receptor with less than 1% of that of testosterone, although DHT is still effective in activating the receptor at sufficiently high concentrations. Moreover, the synthetic androgens mibolerone and metribolone (R-1881), the endogenous androgen 11-ketotestoterone, and the other steroid hormones estradiol and cortisol are all ineffective competitors for the receptor. Since mibolerone and metribolone bind to and activate the nuclear androgen receptor (AR) but not ZIP9, they could potentially be employed to differentiate between AR- and ZIP9-mediated responses of testosterone. The nonsteroidal antiandrogen bicalutamide has been identified as an antagonist of ZIP9.
Clinical significance Zinc homeostasis is very important in human health, because zinc is present in the structure of some proteins like zinc-dependent metalloenzymes and zinc-finger-containing transcriptional factors. In addition, zinc is involved in signalling for cell growth, proliferation, division and apoptosis. As a result, any dysfunction of zinc transporter proteins can be harmful for the cells, and some of them are associated with different cancers, diabetes and inflammation. For instance, through activation of ZIP9, testosterone has been found to increase intracellular zinc levels in breast cancer, prostate cancer, and ovarian follicle cells and to induce apoptosis in these cells, an action which may be mediated partially or fully by increased zinc concentrations.
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