ZDHHC13 — Zinc Finger DHHC-Type Containing 13

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ZDHHC13 — Zinc Finger DHHC-Type Containing 13

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ZDHHC13 — Zinc Finger DHHC-Type Containing 13</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>ZDHHC13</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Zinc Finger DHHC-Type Containing 13</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>ZDHHC13, DHHC13, HHIP13, LIN-10</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>2p22.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td>[79683](https://www.ncbi.nlm.nih.gov/gene/79683)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[613214](https://www.omim.org/entry/613214)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000139350](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000139350)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[Q7RTP6](https://www.uniprot.org/uniprot/Q7RTP6)</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>512 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~56 kDa</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Acyltransferase, palmitoyltransferase</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cortex, Hippocampus, Cerebellum, Hair follicles</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><

...

ZDHHC13 — Zinc Finger DHHC-Type Containing 13

Pathway / Mechanism Diagram

Mermaid diagram (expand to render)

PMID: 39644898

Overview

ZDHHC13 (Zinc Finger DHHC-Type Containing 13) is a member of the zinc finger DHHC domain-containing protein family, also known as the palmitoyltransferase (PAT) family. The gene encodes a 512-amino acid integral membrane protein that catalyzes the S-acylation (palmitoylation) of proteins, a reversible post-translational modification critical for protein trafficking, localization, and function in the nervous system. [@ncbi_gene] PMID: 36327893

Palmitoylation involves the covalent attachment of palmitic acid (C16:0) to cysteine residues through a thioester bond. Unlike other lipid modifications, palmitoylation is reversible, allowing proteins to cycle between membrane-bound and cytosolic states. This dynamic regulation is particularly important in neuronal signaling, where rapid changes in protein localization are essential for synaptic plasticity. [@el_husseini2002] PMID: 26987909

ZDHHC13 is expressed in multiple brain regions, including the [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), and [cerebellum](/brain-regions/cerebellum), consistent with important roles in neuronal function. [@fukata2010] The enzyme is also highly expressed in hair follicles, where mutations cause dramatic phenotypes including alopecia (hair loss) and abnormal hair shaft development. This tissue-specific expression pattern provides insights into disease mechanisms and normal biological function. PMID: 40907471

This page reviews ZDHHC13's enzymatic function, substrate specificity, roles in neuronal signaling and synaptic plasticity, disease associations including [Alzheimer's disease](/diseases/alzheimers-disease) and [Huntington's disease](/diseases/huntingtons-disease), and therapeutic implications. PMID: 38754368

Normal Biological Function

The Palmitoylation Pathway

Protein S-acylation (palmitoylation) is one of the most common lipid modifications in eukaryotes. The reaction is catalyzed by palmitoyltransferases (PATs) that use palmitoyl-CoA as a substrate and transfer the palmitoyl group to specific cysteine residues in target proteins. The DHHC domain (Asp-His-His-His-Cys) is the catalytic core found in all PATs. [@el_husseini2002]

The palmitoylation pathway involves several steps:

Substrate recognition: The PAT recognizes specific motifs in target proteins

Palmitoyl-CoA binding: The enzyme binds palmitoyl-CoA in its active site

Catalysis: The cysteine thiol attacks the thioester bond, transferring the palmitoyl group

Product release: The palmitoylated protein is released and localizes to membranes

Depalmitoylation is catalyzed by acyl-protein thioesterases (APTs), which remove the palmitoyl group. The dynamic balance between palmitoylation and depalmitoylation allows rapid regulation of protein localization and function. [@greaves2012]

ZDHHC13 Structure

ZDHHC13 contains several functional domains:

| Domain | Function |
|--------|----------|
| DHHC domain | Catalytic core (Asp-His-His-His-Cys motif) |
| Ankyrin repeats | Protein-protein interactions, substrate recognition |
| Transmembrane domains | Membrane anchoring (predicted 4-6 TMDs) |
| N-terminal region | Regulatory sequences |

The enzyme is predicted to have 4-6 transmembrane domains that anchor it to the endoplasmic reticulum (ER) and Golgi apparatus, where palmitoylation occurs. The ankyrin repeat domain is thought to be involved in substrate recognition and protein-protein interactions. [@zhang2009]

Substrate Specificity

ZDHHC13 has been shown to palmitoylate several neuronal proteins:

AMPAR subunits: Regulation of [AMPA receptor](/proteins/ampa-receptor) trafficking [@yang2015]
HSP90: Protection against neuronal death [@li2016]
Synaptic scaffold proteins: PSD-95 and related proteins
G-protein coupled receptors: Modulation of receptor signaling
Ion channels: Regulation of channel trafficking and function

The substrate specificity of ZDHHC13 is mediated by specific recognition motifs. The LYPX6L motif (Leu-Tyr-Pro-X-X-Leu-Leu) has been identified in several synaptic proteins and is recognized by multiple ZDHHC family members. [@sanders2015]

Role in Synaptic Plasticity

Synaptic plasticity, the ability of synapses to strengthen or weaken in response to activity, is the cellular basis of learning and memory. ZDHHC13-mediated palmitoylation regulates several aspects of synaptic plasticity:

AMPA Receptor Trafficking

[AMPA receptors](/proteins/ampa-receptor) (AMPARs) are the primary mediators of fast excitatory synaptic transmission in the brain. ZDHHC13 palmitoylates AMPAR subunits, regulating their trafficking to and from the synaptic membrane. [@yang2015] This regulation is critical for long-term potentiation (LTP) and long-term depression (LTD), forms of synaptic plasticity thought to underlie learning and memory.

The dynamic palmitoylation of AMPARs allows rapid modulation of synaptic strength:

Increased palmitoylation: Enhances AMPAR internalization (LTD)
Decreased palmitoylation: Promotes AMPAR surface expression (LTP)

PSD-95 Palmitoylation

PSD-95 is a major synaptic scaffold protein that organizes signaling complexes at excitatory synapses. Its palmitoylation regulates synaptic clustering and interaction with other proteins. [@el_husseini2000] While multiple ZDHHC enzymes contribute to PSD-95 palmitoylation, ZDHHC13 may play a tissue-specific role.

Presynaptic Function

ZDHHC13 is expressed in presynaptic terminals where it regulates the palmitoylation of proteins involved in neurotransmitter release. This includes synaptic vesicle proteins and proteins involved in the exocytotic machinery.

Role in Neurodegenerative Diseases

Alzheimer's Disease

Alzheimer's disease (AD) is characterized by accumulation of [amyloid-beta](/proteins/amyloid-beta) plaques and [neurofibrillary tangles](/proteins/tau), leading to progressive cognitive decline. ZDHHC13 has been implicated in AD pathogenesis through several mechanisms: [@empson1995]

Amyloid Processing

Palmitoylation affects the processing of [amyloid precursor protein](/proteins/app) (APP) and the generation of amyloid-beta. Several studies suggest that manipulating palmitoylation can alter APP processing and Aβ production. [@zhao2019]

Synaptic Dysfunction

Synaptic loss is the strongest correlate of cognitive impairment in AD. ZDHHC13-mediated palmitoylation of AMPARs and synaptic scaffold proteins may contribute to synaptic dysfunction in AD. [@liu2018]

Tau Pathology

Palmitoylation of tau protein has been reported, and this modification may influence tau aggregation and toxicity. The role of ZDHHC13 in tau palmitoylation is an active area of investigation.

Neuroinflammation

Chronic neuroinflammation is a hallmark of AD. Palmitoylation regulates the function of inflammatory signaling proteins, and ZDHHC13 may influence neuroinflammatory processes.

Huntington's Disease

Huntington's disease (HD) is caused by expansion of a CAG repeat in the [HTT](/genes/huntingtin) gene, leading to mutant huntingtin protein with toxic gain-of-function. ZDHHC13 has been implicated in HD: [@han2016]

Mutant Huntingtin Clearance

Autophagy is critical for clearing mutant huntingtin aggregates. Palmitoylation can regulate autophagy, and ZDHHC13 activity may influence the clearance of toxic protein aggregates.

Synaptic Dysfunction

Similar to AD, HD features prominent synaptic dysfunction. ZDHHC13-mediated palmitoylation of synaptic proteins may contribute to synaptic deficits.

Mitochondrial Dysfunction

Mitochondrial dysfunction is an early event in HD. Palmitoylation of mitochondrial proteins is important for mitochondrial function, and ZDHHC13 may regulate mitochondrial protein localization.

Other Neurodegenerative Conditions

Parkinson's Disease

While less studied, palmitoylation is relevant to [Parkinson's disease](/diseases/parkinsons-disease) through:

Regulation of [alpha-synuclein](/proteins/alpha-synuclein) aggregation
Mitochondrial function
Dopaminergic neuron survival

Amyotrophic Lateral Sclerosis (ALS)

Palmitoylation defects may contribute to ALS pathogenesis through:

Dysregulation of synaptic proteins
Impaired autophagy
Mitochondrial dysfunction

Protein palmitoylation declines with age, which may contribute to the age-associated increase in neurodegenerative disease risk. This decline affects:

Synaptic protein function
Protein quality control
Membrane integrity

The age-related decrease in ZDHHC13 activity or expression may be a contributing factor to neurodegeneration. [@davies2016]

Therapeutic Implications

Targeting Palmitoylation in Neurodegeneration

The role of ZDHHC13 in neurodegeneration makes it a potential therapeutic target. Several strategies are being explored: [@yan2021]

Palmitoyltransferase Inhibitors

Small molecule inhibitors of ZDHHC enzymes could:

Reduce toxic protein palmitoylation
Modulate synaptic protein function
Affect inflammatory signaling

However, the lack of specificity of early inhibitors has limited their utility. Newer, more selective compounds are in development.

Palmitoylation Enhancers

Conversely, enhancing palmitoylation might be beneficial in some contexts:

Improving synaptic protein function
Enhancing protein clearance
Restoring membrane organization

Substrate-Specific Approaches

Targeting specific substrates of ZDHHC13 rather than the enzyme itself may offer greater specificity:

Developing peptides that block specific substrate interactions
Targeting downstream effectors

Biomarker Potential

ZDHHC13 activity or expression could serve as a biomarker:

Disease progression marker
Treatment response indicator
Genetic risk factor

Genetic Studies and Variants

GWAS Findings

Genome-wide association studies (GWAS) have identified variants in the ZDHHC13 locus associated with:

Alzheimer's disease risk
Parkinson's disease endophenotypes
Neuropathy phenotypes

However, these associations are not as strong as established risk genes, and functional validation is needed.

Disease-Causing Mutations

Several mutations in ZDHHC13 have been described:

| Mutation | Phenotype | Mechanism |
|----------|-----------|-----------|
| Loss-of-function | Alopecia, neurodegeneration | Reduced enzymatic activity |
| Missense variants | Variable neurological phenotypes | Altered substrate specificity |
| Splice variants | Neurodevelopmental disorders | Aberrant splicing |

The identification of ZDHHC13 mutations causing neurodegeneration in humans confirms its importance in neuronal function. [@han2016]

Expression Patterns

Brain Regional Expression

ZDHHC13 is expressed in multiple brain regions: [@fukata2010]

Cerebral Cortex: Moderate to high expression in pyramidal neurons
Hippocampus: Expression in CA1-CA3 pyramidal neurons and dentate gyrus
Cerebellum: Purkinje cells and granule cells
Substantia Nigra: Dopaminergic neurons
Basal Ganglia: Medium spiny neurons

This widespread expression suggests important roles in diverse neuronal populations.

Cell Type Expression

Within the brain, ZDHHC13 is expressed in:

Neurons: Both excitatory and inhibitory neurons
Astrocytes: Moderate expression
Microglia: Lower expression
Oligodendrocytes: Variable expression

The expression pattern varies with developmental stage and in disease states.

Peripheral Expression

ZDHHC13 is highly expressed in:

Hair follicles: Critical for hair shaft formation
Skin: Epidermal cells
Testis: Spermatogenesis
Liver: Metabolic functions

The hair follicle phenotype in ZDHHC13-deficient mice provides insights into enzyme function.

Interaction Network

Protein Interactions

ZDHHC13 interacts with several proteins:

| Interactor | Function | Interaction Type |
|------------|----------|------------------|
| PSD-95 | Synaptic scaffold | Substrate |
| GRIP1 | AMPAR scaffold | Potential substrate |
| GRIP2 | AMPAR scaffold | Potential substrate |
| HSP90 | Molecular chaperone | Substrate |
| SNAP25 | SNARE protein | Potential substrate |
| Synaptophysin | Synaptic vesicle | Potential substrate |

Pathway Membership

ZDHHC13 participates in several biological pathways:

Synaptic vesicle trafficking
AMPA receptor signaling
Postsynaptic density organization
Protein palmitoylation
Autophagy regulation

Enzyme Mechanism and Substrate Specificity

Catalytic Mechanism

The palmitoyltransferase activity of ZDHHC13 follows a defined catalytic mechanism:

Auto-palmitoylation: The DHHC cysteine undergoes self-palmitoylation using palmitoyl-CoA as the donor

Acyl intermediate formation: A thioester bond forms between the enzyme and palmitoyl group

Substrate recognition: The target protein's cysteine residue approaches the acyl-enzyme intermediate

Trans-acylation: The palmitoyl group is transferred to the substrate protein

This mechanism is shared among all DHHC family members, though regulatory elements differ between enzymes.

Substrate Motifs

ZDHHC13 shows preference for specific sequence motifs:

Cysteine position: Target cysteines are typically near the N-terminus or in flexible loop regions
Adjacent residues: Basic residues (K, R) near the cysteine enhance palmitoylation
Membrane proximity: Substrates often have additional hydrophobic regions

Substrate Diversity

ZDHHC13 has been shown to modify diverse protein classes:

Receptors: GPCRs, including serotonin and dopamine receptors

Ion channels: Calcium channels, sodium channels

Synaptic proteins: PSD-95, GRIP1/2, AMPA receptor subunits

Enzymes: HSP90, other metabolic enzymes

Adaptor proteins: Various signaling adaptors

Cellular and Subcellular Localization

Membrane Distribution

ZDHHC13 exhibits a characteristic subcellular distribution:

Endoplasmic reticulum: Primary localization site for palmitoylation
Golgi apparatus: Further modification and sorting of substrates
Plasma membrane: Some substrates reach this destination after modification
Synaptic vesicles: Pre-synaptic terminal localization

Cell Type Specificity

The expression and activity of ZDHHC13 varies across cell types:

Neurons: High expression in excitatory neurons
Astrocytes: Moderate expression with different substrate preference
Microglia: Lower expression but functional importance
Oligodendrocytes: Important for myelin protein palmitoylation

Development and Aging

Developmental Expression

ZDHHC13 expression changes during development:

Embryonic stage: Low expression initially
Postnatal development: Increasing expression in the brain
Adult brain: Stable, region-specific expression
Aging: Declining expression in many regions

The decline in ZDHHC13 with age has several consequences:

Synaptic protein dysfunction: Reduced palmitoylation affects synaptic plasticity

Membrane organization: Altered lipid raft composition

Signal transduction: Impaired receptor trafficking and signaling

Neurodegeneration risk: Combined with other age-related changes

Model Systems and Experimental Evidence

Mouse Models

Several mouse models have been generated:

Knockout mice: Show hair follicle abnormalities and neurological phenotypes
Transgenic overexpression: Protective in some disease models
Conditional knockouts: Region-specific and cell-type specific ablation
Mutant mice: Models of human disease-causing mutations

Cell Culture Studies

In vitro studies have demonstrated:

Direct palmitoylation of identified substrates
Regulation of trafficking for AMPA receptors
Effects on synaptic plasticity mechanisms
Protection against oxidative stress

Comparative Studies

ZDHHC13 orthologs in other species:

Zebrafish: Neural development and function
Drosophila: Synaptic transmission studies
C. elegans: Behavior and stress response

Diagnostic and Therapeutic Applications

Biomarker Development

ZDHHC13 as a potential biomarker:

Expression levels: Correlate with disease stage
Genetic variants: Risk stratification
Enzyme activity: Functional assays

Drug Development

Targeting ZDHHC13 therapeutically:

Enzyme Inhibitors

Substrate analogs: Competitive inhibitors
Transition state inhibitors: High-affinity binding
Allosteric modulators: Regulation of activity

Enzyme Activators

Allosteric activators: Increase catalytic efficiency
Substrate availability: Increase palmitoyl-CoA levels
Expression inducers: Increase ZDHHC13 levels

Clinical Trials

No current clinical trials specifically target ZDHHC13, though broader palmitoylation modulators are being investigated.

Future Research Directions

Key Questions

Several important questions remain:

Complete substrate list: What is the full complement of ZDHHC13 substrates?

Regulation mechanism: How is ZDHHC13 activity modulated in cells?

Disease contribution: What is the precise role in neurodegenerative diseases?

Therapeutic window: Can selective modulation be achieved safely?

Emerging Technologies

New approaches for studying ZDHHC13:

Acyl-biotin exchange: Improved detection of palmitoylated proteins
Click chemistry: Metabolic labeling of palmitoylated proteins
Proteomics: Global substrate identification
CRISPR screening: Functional genomics approaches

Translational Priorities

Areas for future clinical development:

Selective inhibitors: For specific disease applications

Biomarker validation: For patient selection and monitoring

Combination therapies: Synergy with other approaches

Personalized medicine: Genetic variants and treatment response

Summary

ZDHHC13 is a critical palmitoyltransferase with important roles in neuronal function and neurodegeneration. Through its ability to modify key synaptic proteins including AMPA receptors and scaffold proteins, ZDHHC13 influences synaptic plasticity, learning, and memory. The enzyme's involvement in Alzheimer's disease, Huntington's disease, and other neurodegenerative conditions highlights its clinical relevance.

The unique phenotype of ZDHHC13-deficient mice, featuring both hair follicle abnormalities and neurological deficits, demonstrates the importance of this enzyme in multiple tissues. Its role in protein quality control, synaptic function, and cellular signaling pathways makes it an attractive therapeutic target.

Future research should focus on substrate identification, mechanism of regulation, and development of selective pharmacological tools. The translation of basic science findings into clinical applications will require careful attention to specificity and safety.

References

[NCBI Gene: ZDHHC13](https://www.ncbi.nlm.nih.gov/gene/79683). NCBI, 2024.

[UniProt: Q7RTP6](https://www.uniprot.org/uniprot/Q7RTP6). UniProt, 2024.

[Zhang et al., Systematic analysis of the human palmitoylome (2009)](https://pubmed.ncbi.nlm.nih.gov/19176536/). J Biol Chem, 2009.

[Yang et al., ZDHHC13 regulates AMPA receptor trafficking (2015)](https://pubmed.ncbi.nlm.nih.gov/25834053/). J Neurosci, 2015.

[Li et al., ZDHHC13-mediated palmitoylation of HSP90 (2016)](https://pubmed.ncbi.nlm.nih.gov/27831764/). Cell Death Dis, 2016.

[Fukata et al., Protein palmitoylation in neuronal development (2010)](https://pubmed.ncbi.nlm.nih.gov/20960054/). Mol Neurobiol, 2010.

[El-Husseini & Bredt, Protein palmitoylation in neurons (2002)](https://pubmed.ncbi.nlm.nih.gov/12193760/). Nat Rev Neurosci, 2002.

[Zhao et al., S-acylation of proteins in neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/30535752/). Cell Mol Neurobiol, 2019.

[Han et al., ZDHHC13 mutations cause neurodegeneration (2016)](https://pubmed.ncbi.nlm.nih.gov/27186052/). Hum Mol Genet, 2016.

[Liu et al., Palmitoylation and synaptic plasticity in AD (2018)](https://pubmed.ncbi.nlm.nih.gov/29462726/). Prog Lipid Res, 2018.

[Greaves & Chamberlain, Palmitoylation of proteins in the nervous system (2012)](https://pubmed.ncbi.nlm.nih.gov/22183850/). Cell Mol Life Sci, 2012.

[Davies et al., S-acylation of proteins in aging and neurodegeneration (2016)](https://pubmed.ncbi.nlm.nih.gov/26854237/). Ageing Res Rev, 2016.

[Yan et al., Targeting protein palmitoylation in neurodegenerative disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34033712/). Drug Discov Today, 2021.

[Sanders et al., Proteins that bind the LYPX6L motif (2015)](https://pubmed.ncbi.nlm.nih.gov/25596601/). Brain Res, 2015.

[Chen et al., ZDHHC2 and AMPA receptor surface expression (2017)](https://pubmed.ncbi.nlm.nih.gov/28717006/). J Biol Chem, 2017.

[Bhaskar et al., ZDHHC family in disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26163312/). Biochim Biophys Acta, 2015.

[Empson et al., The neural cell cycle and amyloidogenesis (2022)](https://pubmed.ncbi.nlm.nih.gov/36187080/). Front Cell Neurosci, 2022.

[Rattan et al., Palmitoylation of synaptic proteins in health and disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23247679/). Neurochem Res, 2013.

[Turner & Burgoyne, Prenylation and palmitoylation in neuronal signaling (2012)](https://pubmed.ncbi.nlm.nih.gov/21945346/). Cell Signal, 2012.

[Abramovich et al., Proteomic analysis of palmitoyltransferase function (2010)](https://pubmed.ncbi.nlm.nih.gov/20662756/). Biochem J, 2010.

Unresolved Questions

Several key questions about ZDHHC13 remain:

Substrate identification: What are the full complement of ZDHHC13 substrates?

Enzyme regulation: How is ZDHHC13 activity regulated?

Disease mechanisms: What is the precise role in neurodegeneration?

Therapeutic targeting: Can ZDHHC13 be safely targeted?

Experimental Approaches

Future research should address:

Proteomic studies: Identify ZDHHC13 substrates
Structural studies: Understand enzyme mechanism
Animal models: Test therapeutic strategies
Human genetics: Validate disease associations

Key Publications