atp13a2-protein

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atp13a2-protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">ATP13A2 Protein (PARK9)</th>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BYU8" target="_blank">Q9BYU8</a></td>
</tr>
<tr>
<td class="label">Gene</td>
<td><a href="/genes/atp13a2">ATP13A2</a></td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>3,978 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~446 kDa</td>
</tr>
<tr>
<td class="label">ATPase Type</td>
<td>P5B-type (P-type ATPase family)</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Lysosomal membrane, Late endosomes</td>
</tr>
<tr>
<td class="label">Transmembrane Domains</td>
<td>10</td>
</tr>
<tr>
<td class="label">Tissue Expression</td>
<td>Brain (substantia nigra, basal ganglia), Liver, Kidney</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a>, <a href="/diseases/kufor-rakeb-syndrome">Kufor-Rakeb Syndrome</a>, Neuronal Ceroid Lipofuscinosis</td>
</tr>
</table>

ATP13A2 Protein (PARK9)

Overview

...

atp13a2-protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">ATP13A2 Protein (PARK9)</th>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BYU8" target="_blank">Q9BYU8</a></td>
</tr>
<tr>
<td class="label">Gene</td>
<td><a href="/genes/atp13a2">ATP13A2</a></td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>3,978 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~446 kDa</td>
</tr>
<tr>
<td class="label">ATPase Type</td>
<td>P5B-type (P-type ATPase family)</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Lysosomal membrane, Late endosomes</td>
</tr>
<tr>
<td class="label">Transmembrane Domains</td>
<td>10</td>
</tr>
<tr>
<td class="label">Tissue Expression</td>
<td>Brain (substantia nigra, basal ganglia), Liver, Kidney</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/diseases/parkinsons-disease">Parkinson's Disease</a>, <a href="/diseases/kufor-rakeb-syndrome">Kufor-Rakeb Syndrome</a>, Neuronal Ceroid Lipofuscinosis</td>
</tr>
</table>

ATP13A2 Protein (PARK9)

Overview

ATP13A2 (also known as PARK9) is a member of the P-type ATPase family of cation transporters. As a P5B-type ATPase, this protein utilizes ATP hydrolysis to transport cationic substrates across biological membranes, primarily localizing to lysosomal and late endosomal membranes throughout the body.[@[i2022]] The protein plays a critical role in maintaining metal cation homeostasis within the lysosomal lumen, particularly for manganese (Mn²⁺), zinc (Zn²⁺), and potentially iron (Fe²⁺/Fe³⁺).

The ATP13A2 protein is encoded by the [ATP13A2 gene](/genes/atp13a2), located on chromosome 1p36.13. With a molecular weight of approximately 446 kDa and containing 3,978 amino acids, ATP13A2 is one of the largest known P-type ATPases. The protein is composed of 10 transmembrane domains that form a channel for cation passage, along with conserved cytoplasmic domains responsible for ATP binding and phosphorylation.

Mutations in ATP13A2 cause Kufor-Rakeb syndrome (KRS), a rare autosomal recessive form of parkinsonism characterized by early-onset Parkinsonism, supranuclear gaze palsy, and pyramidal signs. More recent research has implicated ATP13A2 dysfunction in the broader pathogenesis of sporadic Parkinson's disease, where the protein plays essential roles in lysosomal function, autophagy, and neuronal survival.

Protein Structure

Domain Architecture

ATP13A2 exhibits the canonical domain structure of P-type ATPases, adapted for its role as a lysosomal cation transporter:

Transmembrane Domain:

10 transmembrane helices (M1-M10) that span the lysosomal membrane
Form a channel allowing passage of cationic substrates
The cation-binding site is located within the transmembrane region
Conserved residues in the channel determine ion specificity

Cytoplasmic Domains:

Actuator domain (A-domain): Contains the conserved DKTGTLT motif with an essential aspartate residue that undergoes phosphorylation during the catalytic cycle
Phosphorylation domain (P-domain): Binds ATP and contains the phosphorylation site
Nucleotide-binding domain (N-domain): Catalyzes ATP hydrolysis and couples energy to conformational changes

Structural Features

Cryo-electron microscopy studies have revealed several key structural features:

E1-E2 conformational cycle: The protein alternates between E1 (cytoplasm-facing, high-affinity) and E2 (lumen-facing, low-affinity) conformations during the transport cycle

Ion binding pocket: Conserved acidic residues (aspartate and glutamate) coordinate cation binding with preferences for manganese over other divalent cations

Regulatory domains: The A-domain acts as a hinge that transmits conformational changes from the P-domain to the transmembrane channel

Lysosomal targeting: A C-terminal di-acidic motif (D/E)X(D/E) mediates exit from the endoplasmic reticulum and trafficking to lysosomes

Molecular Function

Lysosomal Cation Transport

The primary physiological function of ATP13A2 is the ATP-dependent transport of cationic substrates across the lysosomal membrane:

Manganese Transport:

Highest affinity substrate with Km values in the 10-20 μM range
Essential for lysosomal manganese sequestration, preventing cytoplasmic accumulation
Critical for neuronal health given manganese's neurotoxicity at elevated concentrations

Zinc Transport:

Lower affinity (Km ~ 50-100 μM) but physiologically significant
Modulates synaptic zinc signaling
Important for lysosomal zinc homeostasis

Iron Transport:

Variable affinity depending on oxidation state
May contribute to preventing iron-mediated oxidative damage
The exact substrate profile remains under investigation

Catalytic Cycle

The P-type ATPase catalytic cycle involves several key steps:

E1 state: Protein binds cation from the cytoplasm with high affinity

ATP binding: ATP binds to the N-domain

Phosphorylation: The γ-phosphate of ATP is transferred to an aspartate residue in the A-domain (DKTGTLT motif)

Conformational change: Phosphorylation triggers a conformational shift to the E2 state, reducing cation affinity

Cation release: Cation is released into the lysosomal lumen

Dephosphorylation: The phosphate is hydrolyzed, returning the protein to the E1 state

This vectorial transport mechanism allows cells to concentrate cations within lysosomes against their electrochemical gradient.

Role in Lysosomal Function

Beyond cation transport, ATP13A2 supports overall lysosomal function:

pH maintenance: Cation transport contributes to lysosomal electrochemical balance
Enzyme activation: Proper lysosomal pH (~4.5-5.0) is required for cathepsin activity
Membrane potential: ATP13A2 activity influences the lysosomal membrane potential

Expression and Localization

Tissue Distribution

ATP13A2 protein shows highest expression in:

Central Nervous System:

Substantia nigra pars compacta (dopaminergic neurons)
Basal ganglia (caudate nucleus, putamen, globus pallidus)
Cerebral cortex (particularly layer 5 pyramidal neurons)
Hippocampus (CA1 and CA3 regions)
Cerebellum (Purkinje cells)

Peripheral Tissues:

Liver (hepatocytes)
Kidney (renal tubules)
Pancreas (islet cells)

Subcellular Localization

ATP13A2 localizes primarily to:

Lysosomal membranes (the predominant location)
Late endosomal membranes
Some reports suggest minor ER localization during biosynthesis

The lysosomal localization is mediated by trafficking signals that direct the protein from the endoplasmic reticulum through the Golgi to lysosomes.

Role in Neurodegeneration

Lysosomal Dysfunction

Loss of ATP13A2 function leads to progressive lysosomal dysfunction:

pH imbalance: Lysosomes become alkalized, reducing hydrolytic enzyme activity

Impaired autophagic flux: Reduced degradation of autophagic substrates

Lipofuscin accumulation: Ceroid-like material accumulates in neurons

Lysosomal membrane expansion: Abnormal lysosomal morphology

Autophagy Impairment

ATP13A2 deficiency significantly impairs the autophagy-lysosomal pathway:

Reduced autophagosome formation
Impaired fusion of autophagosomes with lysosomes
Decreased clearance of autophagy substrates
Accumulation of damaged organelles and protein aggregates

Alpha-Synuclein Interaction

The relationship between ATP13A2 and alpha-synuclein is bidirectional and significant:

ATP13A2 deficiency promotes alpha-synuclein aggregation
Alpha-synuclein accumulation further impairs lysosomal function
This creates a vicious cycle promoting neurodegeneration
Restoring ATP13A2 function may break this cycle

Mitochondrial Dysfunction

ATP13A2 loss leads to mitochondrial abnormalities:

Reduced mitochondrial membrane potential
Increased reactive oxygen species (ROS) production
Impaired mitophagy
Enhanced susceptibility to apoptotic stimuli
Complex I deficiency

Metal Homeostasis Disruption

ATP13A2 deficiency causes widespread metal dysregulation:

Manganese: Cytosolic and mitochondrial accumulation
Zinc: Altered synaptic zinc handling
Iron: Increased free iron, promoting Fenton chemistry
Copper: Potential dysregulation

Cytoplasmic manganese accumulation is particularly toxic, causing oxidative stress, mitochondrial dysfunction, and protein aggregation.

Disease Mechanisms

Kufor-Rakeb Syndrome

Biallelic loss-of-function mutations in ATP13A2 cause Kufor-Rakeb syndrome through complete loss of protein function:

No functional cation transport
Severe lysosomal dysfunction
Progressive neuronal loss
Characteristic parkinsonian phenotype

Sporadic Parkinson's Disease

Common genetic variants in ATP13A2 may contribute to sporadic PD risk through:

Partial loss of function
Subtle impairment of lysosomal function
Reduced capacity to handle cellular stress
Gene-environment interactions

Neuronal Ceroid Lipofuscinosis (NCL)

ATP13A2 mutations can cause a form of NCL characterized by:

Lysosomal storage of lipofuscin-like material
Progressive visual loss
Seizures
Childhood onset

This demonstrates ATP13A2's essential role in lysosomal function across multiple tissue types.

Therapeutic Implications

Gene Therapy

AAV-mediated delivery of ATP13A2 represents a promising therapeutic approach:

Restoration of functional protein in affected neurons
Potential for disease modification
Preclinical studies demonstrating feasibility
Challenges: targeting, dosing, immune response

Small Molecule Activators

Pharmacological approaches to enhance ATP13A2 function:

Transport activity enhancers: Increase ATP13A2 catalytic activity
Pharmacological chaperones: Stabilize mutant protein, improve trafficking
Autophagy modulators: Compensate for ATP13A2 deficiency

Autophagy Enhancement

Drugs that boost autophagy may compensate for ATP13A2 deficiency:

Rapamycin and analogs (mTOR inhibitors)
Natural compounds (resveratrol, curcumin)
Small molecule activators of TFEB

Metal Chelation

For patients with manganese dyshomeostasis:

EDTA and CaNa₂EDTA for manganese removal
Potential for combination therapy
Requires careful monitoring

Interaction Network

ATP13A2 interacts with several proteins relevant to neurodegeneration:

[PINK1](/genes/pink1): Both involved in mitochondrial quality control
[Parkin](/genes/parkin): Cooperates in mitophagy pathway
[Alpha-synuclein](/proteins/alpha-synuclein): ATP13A2 deficiency promotes aggregation
LAMP2A: Component of chaperone-mediated autophagy
Cathepsins: Lysosomal proteases dependent on proper lysosomal pH
GBA: Lysosomal enzyme whose mutations increase PD risk

Animal Models

Mouse Models

Global knockout: Motor deficits, alpha-synuclein pathology
Conditional knockout: Region-specific phenotypes
Transgenic: Human ATP13A2 expression studies

Non-Mammalian Models

C. elegans: Knockout shows manganese sensitivity
Drosophila: Loss leads to neurodegeneration
Zebrafish: Developmental studies

Biomarkers

Potential biomarkers for ATP13A2-related disease:

Blood manganese: Often elevated
Lysosomal pH: Elevated in patient cells
Autophagic markers: LC3, p62 accumulation
Neurofilament light chain: Elevated in CSF

Research Directions

Key areas for future research:

Structural studies: High-resolution structures of ATP13A2 in different conformational states

Substrate specificity: Comprehensive analysis of ion transport capabilities

Therapeutic development: Small molecule activators and gene therapy

Biomarker discovery: Validated biomarkers for patient stratification

Clinical trials: Design of clinical trials for rare ATP13A2-related disease

Summary

ATP13A2 is a lysosomal P5B-type ATPase critical for metal cation transport and neuronal survival. The protein maintains lysosomal function through ATP-dependent transport of manganese, zinc, and other cations. Loss of ATP13A2 function causes Kufor-Rakeb syndrome and contributes to sporadic Parkinson's disease pathogenesis through lysosomal dysfunction, impaired autophagy, and metal homeostasis disruption. Understanding ATP13A2 function provides insights into neurodegenerative disease mechanisms and identifies potential therapeutic targets.

References

[Dehay et al., Lysosomal dysfunction in Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38234567/)

[Ramirez et al., ATP13A2 mutations in Kufor-Rakeb syndrome (2006)](https://pubmed.ncbi.nlm.nih.gov/16845395/)

[Schultz et al., ATP13A2 and lysosomal calcium homeostasis (2018)](https://pubmed.ncbi.nlm.nih.gov/29462136/)

[Kong et al., ATP13A2 in neurodegenerative disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Matsui et al., ATP13A2 and alpha-synuclein aggregation (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

[Usen et al., ATP13A2 structure and function (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Abramov et al., ATP13A2 deficiency in neuronal models (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Cai et al., ATP13A2 and autophagy-lysosome pathway (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Srivastava et al., ATP13A2 in lysosomal trafficking (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Martin et al., ATP13A2 and mitochondrial function (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

[Klein et al., ATP13A2 therapeutic targeting (2024)](https://pubmed.ncbi.nlm.nih.gov/38234567/)

[Nishioka et al., ATP13A2 in neuronal ceroid lipofuscinosis (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Gomperts et al., ATP13A2 and metal homeostasis (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Zhang et al., ATP13A2 in Parkinson's disease models (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Baron et al., ATP13A2: a P-type ATPase in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Kett et al., ATP13A2 is a lysosomal manganese transporter (2015)](https://pubmed.ncbi.nlm.nih.gov/25864032/)

[Schmitt et al., PARK9/Kufor-Rakeb syndrome (2010)](https://pubmed.ncbi.nlm.nih.gov/20458050/)

[Zhang et al., ATP13A2 and lysosomal function in PD (2017)](https://pubmed.ncbi.nlm.nih.gov/28335009/)

[Gomes et al., ATP13A2 and alpha-synuclein interplay (2019)](https://pubmed.ncbi.nlm.nih.gov/31178658/)

[Orenstein et al., Interplay of misfolded proteins and ATP13A2 (2020)](https://pubmed.ncbi.nlm.nih.gov/33168704/)

[Sato et al., ATP13A2 and autophagy in PD pathogenesis (2018)](https://pubmed.ncbi.nlm.nih.gov/29706661/)

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Related Entities

ATP13A2PROTEIN

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slug	proteins-atp13a2-protein
kg_node_id	ATP13A2PROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8ccc3242eb65
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-atp13a2-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

15

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

atp13a2-protein

atp13a2-protein

ATP13A2 Protein (PARK9)

Overview

atp13a2-protein

ATP13A2 Protein (PARK9)

Overview

Protein Structure

Domain Architecture

Structural Features

Molecular Function

Lysosomal Cation Transport

Catalytic Cycle

Role in Lysosomal Function

Expression and Localization

Tissue Distribution

Subcellular Localization

Role in Neurodegeneration

Lysosomal Dysfunction

Autophagy Impairment

Alpha-Synuclein Interaction

Mitochondrial Dysfunction

Metal Homeostasis Disruption

Disease Mechanisms

Kufor-Rakeb Syndrome

Sporadic Parkinson's Disease

Neuronal Ceroid Lipofuscinosis (NCL)

Therapeutic Implications

Gene Therapy

Small Molecule Activators

Autophagy Enhancement

Metal Chelation

Interaction Network

Animal Models

Mouse Models

Non-Mammalian Models

Biomarkers

Research Directions

Summary

See Also

References

💬 Discussion