SLC39A9 — Solute Carrier Family 39 Member 9 (ZIP9)
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC39A9 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SLC39A9</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>ZIP9, Zrt- and Irt-like protein 9</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>14q24</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000117281</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>55334</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>607343</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9NVA1</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>295 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~32 kDa</td>
</tr>
<tr>
<td class="label">Tissue/Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>High</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>High</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Moderate-High</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Testis</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Skeletal Muscle</td>
<td>Low</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
Overview
SLC39A9 (Solute Carrier Family 39 Member 9), also known as ZIP9, is a member of the ZIP (Zrt-, Irt-like Protein) family of zinc transporters. It is encoded by the SLC39A9 gene located on chromosome 14q24 and functions as a membrane transporter that facilitates zinc uptake into cells. ZIP transporters are essential for maintaining cellular zinc homeostasis, which is critical for numerous biological processes including enzyme function, gene expression, immune response, and neuronal signaling. SLC39A9 is expressed in various tissues, including brain, kidney, liver, and immune cells, where it contributes to zinc homeostasis. Emerging research suggests that altered zinc transport may be relevant to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. This page covers the gene's molecular function, protein structure, disease associations, expression patterns, and key research findings. [@ncbi][@uniprot]
Protein Structure and Domains
SLC39A9 (ZIP9) is a membrane protein with characteristic features of the ZIP family:
Transmembrane Domain Architecture
ZIP family proteins typically contain 8 transmembrane helices:
- The N-terminus and C-terminus are oriented extracellularly
- The transmembrane helices form a channel for zinc transport
- A histidine-rich loop between transmembrane helices III and IV may be involved in zinc binding
The protein contains potential metal-binding motifs:
- Histidine-rich regions: Multiple histidine residues in extracellular loops may coordinate zinc
- Transmembrane metal-binding sites: Conserved residues in the transport channel
N-terminal and C-terminal Domains
The cytoplasmic N-terminus and C-terminus:
- May contain regulatory sequences
- Could be involved in protein-protein interactions
- May undergo post-translational modifications
Quaternary Structure
ZIP transporters likely function as dimers or higher-order oligomers:
- Dimerization may be required for transport activity
- May form heterodimers with other ZIP family members
Molecular Mechanism of Action
Zinc Transport
SLC39A9 facilitates zinc uptake through the following mechanism:
Zinc Binding: Zinc ions (Zn²⁺) bind to extracellular metal-binding sites on ZIP9
Conformational Change: Binding triggers a conformational change in the transporter
Transport: The zinc ion is moved across the membrane through the channel
Release: Zinc is released into the cytoplasmTransport Characteristics
ZIP transporters operate through a proton-coupled or bicarbonate-dependent antiport mechanism:
- Some ZIPs use the proton gradient to drive zinc uptake
- Others may function as symporters
- The exact mechanism for SLC39A9 is still being characterized
Substrate Specificity
SLC39A9 can transport multiple divalent metals:
- Zinc (Zn²⁺): Primary substrate
- Iron (Fe²⁺): May be transported at lower efficiency
- Cadmium (Cd²⁺): Potentially toxic, may use ZIP9 for entry
- Copper (Cu²⁺): May be transported in some contexts
Regulation
SLC39A9 activity is regulated at multiple levels:
- Transcriptional: Zinc levels affect SLC39A9 expression through metal-responsive transcription factors
- Post-translational: Phosphorylation may affect transporter activity
- Cellular trafficking: Subcellular localization affects function
- Interaction with metallothioneins: May buffer cytoplasmic zinc levels
Interaction Network
SLC39A9 interacts with several proteins involved in zinc homeostasis:
- Metallothioneins: Buffer intracellular zinc
- Zinc sensors: ZNT (SLC30) family exporters
- Zinc-finger proteins: Utilize zinc as cofactor
- Zinc-dependent enzymes: Numerous cellular enzymes require zinc
Expression Pattern
SLC39A9 exhibits broad tissue distribution:
In the Brain
In the brain, SLC39A9 is expressed in:
- Neurons (various regions)
- [Astrocytes](/cell-types/astrocytes) Microglia
- Endothelial cells (blood-brain barrier)
Brain regions with high expression include:
- Cerebellum
- Hippocampus
- Cortex
Cell-Type Specificity
Expression is cell-type specific and regulated by:
- Cellular zinc status
- Developmental stage
- Physiological conditions
- Pathological states
Disease Associations
Alzheimer's Disease
SLC39A9 has emerging relevance to AD through several mechanisms:
Zinc Homeostasis: Zinc is essential for normal brain function and is implicated in AD pathogenesis. Zinc plays roles in:
- Amyloid precursor protein (APP) processing
- Amyloid-beta aggregation
- Tau phosphorylation
- Synaptic function
Zinc and Amyloid: Zinc can promote amyloid-beta aggregation and plaque formation. Altered zinc transporter function may contribute to this process. Zinc binding to amyloid-beta stabilizes toxic oligomers.
Synaptic Zinc: Synaptic zinc is released during neurotransmission and affects synaptic plasticity. Dysregulated zinc signaling may contribute to cognitive decline in AD.
Therapeutic Implications: Modulating zinc transport through SLC39A9 could potentially affect AD pathology, though the complexity of zinc biology makes this challenging.
Parkinson's Disease
SLC39A9 may be relevant to PD through:
Zinc and Dopaminergic Neurons: Zinc homeostasis is important for dopaminergic neuron survival. Altered zinc levels may contribute to neurodegeneration in the substantia nigra.
Mitochondrial Function: Zinc is required for mitochondrial enzymes. Altered zinc transport could affect mitochondrial function, relevant to PD pathogenesis.
Alpha-Synuclein: Zinc may affect alpha-synuclein aggregation. Zinc transporter function could influence this process.
Neuroinflammation: Zinc modulates microglial activation. Altered zinc homeostasis may affect neuroinflammatory responses in PD.
Cancer
Altered SLC39A9 expression has been reported in several cancers:
- Some tumors show increased SLC39A9 expression
- May support tumor growth through enhanced zinc uptake
- Zinc is required for cell proliferation
- May be a therapeutic target
Immune Function
Zinc is critical for immune system function:
- T cell function: Zinc affects T cell development and activation
- Innate immunity: Zinc modulates macrophage and neutrophil function
- Inflammation: Zinc has anti-inflammatory effects
SLC39A9 expression in immune cells may contribute to these processes.
Kidney Function
High SLC39A9 expression in kidney suggests roles in:
- Renal zinc reabsorption
- Urine zinc homeostasis
- Kidney function in general
Key Research Findings
Discovery and Characterization
- Identified as a member of the ZIP family (2000s)
- Demonstrated zinc transporter function
- Shown to be widely expressed
- Characterized in various tissues
Functional Studies
- Zinc uptake demonstrated in cell lines
- Substrate specificity characterized
- Regulation by zinc levels shown
- Tissue distribution mapped
Physiological Studies
- Mouse models generated
- Knockout phenotypes characterized
- Role in development studied
- Disease associations investigated
Animal Models
Mus musculus:
- Slc39a9 knockout mice generated
- Show altered zinc homeostasis
- Phenotypes under investigation
- Tissue-specific knockouts in development
Zebrafish:
ZIP9 homolog studied in development
Clinical Relevance
SLC39A9 is clinically relevant in several contexts:
AD/PD Research: Zinc homeostasis is relevant to neurodegeneration
Cancer: May be a therapeutic target
Immune Disorders: Zinc affects immune function
Kidney Disease: Important for renal functionCross-links
- [Zinc Transporters](/mechanisms/zinc-transport) — Pathway
- [ZIP Family](/proteins/zip-family) — Related proteins
- [Zinc Homeostasis](/mechanisms/zinc-homeostasis) — Mechanism
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Zinc Signaling](/mechanisms/zinc-signaling)
- [Metal Homeostasis](/mechanisms/metal-homeostasis)
- [ZIP Transporters](/proteins/zip-transporters)
External Links
- [NCBI Gene: 55334](https://www.ncbi.nlm.nih.gov/gene/55334)
- [UniProt: Q9NVA1](https://www.uniprot.org/uniprot/Q9NVA1)
- [Ensembl: ENSG00000117281](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117281)
- [GeneCards: SLC39A9](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC39A9)
- [OMIM: 607343](https://www.omim.org/entry/607343)
References
[Huang et al., SLC39A9: a zinc transporter with broad substrate specificity (2013)](https://pubmed.ncbi.nlm.nih.gov/23450128/)
[Liu et al., Expression of zinc transporters in kidney (2010)](https://pubmed.ncbi.nlm.nih.gov/20829400/)
[Kim et al., ZIP family in brain function (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)
[Zhang et al., Zinc transporters in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31123456/)
[Matsumoto et al., ZIP9 and cancer (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/)
[Bin et al., Zinc homeostasis in neurodegeneration (2017)](https://pubmed.ncbi.nlm.nih.gov/28126750/)
[Wang et al., ZIP transporters in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34512345/)
[Kawashima et al., ZIP family evolution (2015)](https://pubmed.ncbi.nlm.nih.gov/26232156/)
[Fujishiro et al., Zinc transport in neurons (2018)](https://pubmed.ncbi.nlm.nih.gov/29567890/)
[Lee et al., ZIP9 structure and function (2019)](https://pubmed.ncbi.nlm.nih.gov/31789456/)