SLC39A9 Gene

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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

...

SLC39A9 — Solute Carrier Family 39 Member 9 (ZIP9)

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]

Gene Information

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

Metal-Binding Sites

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 cytoplasm

Transport 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 function

Cross-links

[Zinc Transporters](/mechanisms/zinc-transport) — Pathway
[ZIP Family](/proteins/zip-family) — Related proteins
[Zinc Homeostasis](/mechanisms/zinc-homeostasis) — Mechanism

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/)

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SLC39A9 Gene

SLC39A9 — Solute Carrier Family 39 Member 9 (ZIP9)

SLC39A9 — Solute Carrier Family 39 Member 9 (ZIP9)

Overview

Gene Information

Protein Structure and Domains

Transmembrane Domain Architecture

Metal-Binding Sites

N-terminal and C-terminal Domains

Quaternary Structure

Molecular Mechanism of Action

Zinc Transport

Transport Characteristics

Substrate Specificity

Regulation

Interaction Network

Expression Pattern

In the Brain

Cell-Type Specificity

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Cancer

Immune Function

Kidney Function

Key Research Findings

Discovery and Characterization

Functional Studies

Physiological Studies

Animal Models

Clinical Relevance

Cross-links

See Also

External Links

References