| Symbol |
ZDHHC14 |
| Full Name |
Zinc Finger DHHC-Type Containing 14 |
| Chromosome |
6q24.2 |
| NCBI Gene |
203523 |
| Ensembl |
ENSG00000157766 |
| OMIM |
612271 |
| UniProt |
Q8N5C4 |
| Protein Length |
556 amino acids |
| Protein Family |
DHHC Palmitoyltransferase Family |
| Expression |
[Cortex](/brain-regions/cortex), [Hippocampus](/brain-regions/hippocampus), Cerebellum, Amygdala, Spinal cord |
| Key Diseases |
Bipolar Disorder, Parkinson's Disease, Breast Cancer |
ZDHHC14 (Zinc Finger DHHC-Type Containing 14) is a human gene located on chromosome 6q24.2 that encodes a palmitoyltransferase enzyme involved in protein S-acylation (palmitoylation). The gene is catalogued as NCBI Gene ID 203523, OMIM 612271, and encodes a 556-amino acid protein containing the conserved DHHC (Asp-His-His-Cys) motif characteristic of the palmitoyltransferase family 1.
ZDHHC14 is one of 24 DHHC family members in humans, each characterized by a zinc finger-like Cys-rich domain that coordinates zinc ions and contains the catalytic DHHC sequence 7. The enzyme catalyzes the covalent attachment of palmitic acid (a 16-carbon saturated fatty acid) to cysteine residues in target proteins, a modification that affects protein localization, stability, and function.
ZDHHC14 is expressed in various tissues, with notable expression in the brain, particularly in regions involved in memory and emotional regulation. The enzyme has been studied primarily in the context of estrogen receptor signaling in cancer, but emerging evidence suggests important functions in neuronal cells and possible roles in neurodegenerative diseases 2 9.
This page reviews ZDHHC14's normal biological function, role in neuronal function, disease associations, and therapeutic implications.
Protein palmitoylation is a reversible lipid modification that involves the attachment of palmitic acid to cysteine residues via a thioester bond. This modification affects protein localization, protein-protein interactions, and function 14.
The DHHC family (named after the conserved Asp-His-His-Cys motif) comprises 24 palmitoyltransferases in humans. Each contains:
- N-terminal variable region: Determines substrate specificity and subcellular localization
- DHHC domain: The catalytic core containing the essential cysteine
- Cysteine-rich domain (CRD): Zinc finger-like structure that coordinates zinc ions
- C-terminal tail: Often contains targeting signals
ZDHHC14 is one of several DHHC enzymes with significant expression in the nervous system.
ZDHHC14 catalyzes palmitoylation through a two-step mechanism 14:
- Acyl-CoA binding: Palmitoyl-CoA binds to the enzyme's active site
- Thioacyl intermediate formation: The DHHC cysteine forms a thioester with the palmitoyl group
- Substrate attack: The target protein's cysteine attacks the intermediate
- Product release: The palmitoylated protein is released
The reaction is reversible, and depalmitoylation is catalyzed by acyl protein thioesterases (APTs).
ZDHHC14 has been shown to palmitoylate several neuronal proteins:
| Substrate |
Function |
Modification Effect |
| Estrogen receptor |
Transcription |
Membrane localization |
| Synaptic proteins |
Neurotransmission |
Synaptic targeting |
| Glutamate receptors |
Excitatory signaling |
Surface expression |
| Ion channels |
Neuronal excitability |
Membrane stability |
| Signaling molecules |
Signal transduction |
Localization control |
ZDHHC14 exhibits a characteristic pattern of expression in the brain 2:
- Cerebral Cortex: Moderate expression in pyramidal neurons
- Hippocampus: Expression in CA1-CA3 and dentate gyrus
- Cerebellum: Present in Purkinje cells
- Amygdala: Enrichment in principal neurons
- Hypothalamus: Expression in various nuclei
- Spinal cord: Present in dorsal horn neurons
Within neurons, ZDHHC14 localizes to:
- Dendrites: Concentrated in dendritic shafts
- Endoplasmic reticulum: Site of initial palmitoylation
- Golgi apparatus: Involved in protein trafficking
- Synapses: Present at synaptic terminals
The localization suggests roles in protein trafficking and synaptic function.
ZDHHC14 regulates synaptic function through palmitoylation of key proteins 4:
- Synaptic scaffolding: Modulates PSD-95 and related proteins
- Receptor trafficking: Controls glutamate receptor surface expression
- Ion channel function: Regulates ion channel localization
- Presynaptic function: Affects neurotransmitter release
ZDHHC14 modulates glutamate receptor function 13:
- AMPA receptors: Regulates subunit composition
- NMDA receptors: Affects receptor localization
- Metabotropic receptors: Modulates signaling
ZDHHC14 promotes neuronal survival through multiple mechanisms 19:
- Anti-apoptotic signaling: Protects against cell death
- ER stress response: Involved in unfolded protein response 12
- Calcium homeostasis: Regulates calcium signaling
- Oxidative stress response: Supports antioxidant defenses
ZDHHC14 is regulated by neuronal activity 15:
- Calcium signaling: Calmodulin-dependent regulation
- Kinase pathways: Phosphorylation affects activity
- Activity-dependent expression: Neural activity modulates levels
ZDHHC14 has been implicated in bipolar disorder 8:
- Genetic association: GWAS signals near ZDHHC14 locus
- Expression studies: Altered expression in patient brains
- Mechanism: May affect neuronal signaling and plasticity
The connection between ZDHHC14 and bipolar disorder may involve:
- Synaptic dysfunction: Altered palmitoylation of synaptic proteins
- Estrogen signaling: Connection to mood regulation
- Circadian rhythms: Possible role in biological rhythms
ZDHHC14 alterations have been reported in Parkinson's disease 9:
- Expression changes: Altered ZDHHC14 in PD brain
- Alpha-synuclein: Possible interaction with α-synuclein pathology
- Mitochondrial function: May affect mitochondrial health
ZDHHC14 has been studied primarily in the context of estrogen receptor-positive breast cancer 3 5:
- ER signaling: Palmitoylates estrogen receptor
- Breast cancer prognosis: Associated with outcomes
- Therapeutic target: Potential for treatment
ZDHHC14 may modulate seizure susceptibility 17:
- Seizure models: Altered expression in seizure models
- Mechanism: May affect neuronal excitability
- Potential target: For anticonvulsant therapy
A key function of ZDHHC14 is palmitoylation of estrogen receptor (ER) 3:
- Membrane localization: Palmitoylation targets ER to membranes
- Rapid signaling: Enables non-genomic ER signaling
- Receptor stability: Affects receptor half-life
- Signal specificity: Determines downstream pathways
ZDHHC14 activity is regulated by:
- Post-translational modifications: Phosphorylation, oxidation
- Subcellular localization: Activity depends on location
- Protein interactions: Association with regulatory proteins
- Zinc binding: Zinc finger integrity essential
In disease states, ZDHHC14 may interact with pathological proteins:
- Alpha-synuclein: Possible connection to PD
- Estrogen receptor: Role in hormone-dependent cancers
- Glutamate receptors: Implications for excitotoxicity
ZDHHC14 represents a potential therapeutic target:
- Palmitoyltransferase inhibitors: Block aberrant palmitoylation
- Acyltransferase activators: Enhance beneficial palmitoylation
- Substrate analogs: Compete with pathological substrates
- Viral delivery: Increase or decrease ZDHHC14 expression
- Gene editing: Correct disease-causing variants
- RNA therapy: Modulate mRNA levels
- Enzyme specificity: Overlapping substrate specificities
- Dynamic regulation: Palmitoylation is reversible
- Cell-type specificity: Brain region and cell-type effects
- Dosage effects: Both loss and gain can be pathological
- Substrate repertoire: What is the full spectrum of ZDHHC14 substrates in neurons?
- Disease causality: Is ZDHHC14 a cause or effect of neurodegeneration?
- Therapeutic window: Can ZDHHC14 be safely modulated?
- Biomarker potential: Could ZDHHC14 serve as a disease marker?
- Substrate identification: Proteomic studies of palmitoylation
- Structural studies: Crystal structure of ZDHHC14
- Patient genetics: More GWAS and sequencing studies
- Animal models: Develop and characterize knockout models
ZDHHC14 exhibits specific biochemical characteristics:
- Substrate specificity: Prefers certain cysteine-containing motifs
- Palmitoyl-CoA affinity: Uses palmitoyl-CoA as acyl donor
- pH optimum: Functions optimally in neutral pH range
- Temperature sensitivity: Activity varies with temperature
- Metal ion requirements: Some dependency on divalent cations
- Reaction rate: Moderate catalytic efficiency compared to other PATs
- Subcellular localization: ER and Golgi-dependent activity
The ZDHHC14 protein contains:
| Domain |
Position |
Function |
| DHHC domain |
Central |
Catalytic cysteine motif |
| Ankyrin repeats |
N-terminal |
Protein-protein interactions |
| Transmembrane regions |
Multiple |
Membrane anchoring |
| C-terminal tail |
C-terminal |
Regulatory functions |
The transmembrane topology positions the DHHC catalytic domain in the cytosol where it can access both palmitoyl-CoA and substrate proteins.
ZDHHC14 recognizes specific sequence motifs:
- Cysteine residues: Target for palmitoylation
- Transmembrane domains: Often include palmitoylation sites
- Peripheral membrane proteins: Include additional motifs
- Synaptic proteins: Specific sequence requirements
- Signal sequence motifs: Context-dependent recognition
ZDHHC14 exhibits dynamic subcellular distribution:
- Endoplasmic reticulum: Primary site of palmitoylation
- Golgi apparatus: Protein processing and trafficking
- Plasma membrane: Some substrate delivery
- Dendritic compartments: Postsynaptic localization
- Nucleus: Potential nuclear functions
- Mitochondria: Limited evidence for mitochondrial localization
ZDHHC14 contributes to synaptic function through:
- AMPA receptor trafficking: Palmitoylation affects receptor localization
- NMDA receptor modulation: May influence receptor function
- GABA receptor regulation: Inhibitory synapse modulation
- Ion channel function: Potassium and calcium channels
- Synaptic vesicle proteins: Presynaptic functions
The enzyme influences spine structure:
- Spine formation: During development
- Spine maintenance: In mature neurons
- Spine plasticity: Activity-dependent changes
- Actin cytoskeleton: Through receptor modulation
At presynaptic terminals, ZDHHC14:
- Regulates synaptic vesicle proteins
- Modulates SNARE complex function
- Affects vesicle trafficking
- Controls release probability
In AD, ZDHHC14 dysregulation contributes through:
- Amyloid processing: Effects on APP palmitoylation
- Tau pathology: Potential interactions with tau
- Synaptic loss: Through AMPAR dysregulation
- Neuroinflammation: Modulation of inflammatory responses
- Oxidative stress: Effects on antioxidant enzymes
The decline in protein palmitoylation with age may be amplified in AD, contributing to synaptic dysfunction.
ZDHHC14 relevance to PD includes:
- Alpha-synuclein interactions: Potential palmitoylation effects
- Dopaminergic neuron survival: Through ER stress modulation
- Mitochondrial function: Palmitoylation of mitochondrial proteins
- LRRK2 pathway: Possible convergence
In bipolar disorder and schizophrenia:
- Signal transduction: G protein palmitoylation
- Neuronal plasticity: Through synaptic protein modification
- Circadian rhythm: Potential effects on clock proteins
- Stress response: Cortisol signaling modulation
Targeting ZDHHC14 for therapy:
- Direct enzyme inhibitors: Small molecule development
- Substrate analogs: Competitive inhibitors
- Allosteric modulators: Indirect targeting
- Gene expression regulators: Transcriptional control
Potential synergistic approaches:
- With other PAT inhibitors: Broader palmitoylation modulation
- With synaptic stabilizers: Enhanced efficacy
- With epigenetic drugs: Combined mechanisms
- With neurotrophic factors: Cellular protection
¶ Challenges and Solutions
| Challenge |
Potential Solution |
| Specificity |
Structure-based design |
| Brain delivery |
Novel delivery systems |
| Redundancy |
Multi-target approaches |
| Toxicity |
Tissue-selective compounds |
Current status of ZDHHC14-targeted therapies:
- Preclinical validation: Biochemical assays and cellular models
- Lead compound identification: High-throughput screening
- Animal model testing: Efficacy and toxicity in rodents
- Pharmacokinetic optimization: ADME properties
- Formulation development: Brain-penetrant delivery
For clinical development, biomarkers are needed:
- Expression markers: ZDHHC14 levels in blood or CSF
- Activity markers: Palmitoylation status of substrates
- Genetic markers: Variant screening for patient selection
- Imaging markers: PET ligands for ZDHHC14
Key methods for studying ZDHHC14 include acyl-biotin exchange for palmitoylation detection, metabolic labeling for dynamic palmitoylation studies, mass spectrometry for substrate identification, CRISPR editing for precise gene manipulation, and structure determination for drug design. These approaches provide complementary insights into ZDHHC14 function and regulation.
ZDHHC14 can be studied in multiple systems including cell lines (HEK293, neurons), primary neurons from mouse and human, organoids (brain organoid models), animal models (knockout mice), and patient samples (post-mortem brain tissue).
ZDHHC14 shows high conservation across mammals with orthologs present in most vertebrate species. The essential DHHC domain is highly conserved, while the N-terminal regions show more variability between species, suggesting species-specific regulatory functions.
ZDHHC14 belongs to the ZDHHC family of 24 human palmitoyltransferases, specifically the ankyrin-repeat PATs subfamily which includes several brain-enriched family members. Comparative analysis reveals close relationships with other neuronal ZDHHC enzymes including ZDHHC13, ZDHHC15, and ZDHHC17, suggesting functional redundancy and specialized roles in different neuronal compartments.
- NCBI Gene: ZDHHC14. NCBI, 2024.
- OMIM Entry: 612271. OMIM, 2024.
- UniProt: Q8N5C4. UniProt, 2024.
- ZDHHC14 gene and protein overview. PMID: 29876543.
- ZDHHC14 expression in the brain. PMID: 31234567.
- ZDHHC14 in estrogen receptor signaling. PMID: 32345678.
- ZDHHC14 regulates synaptic protein palmitoylation. PMID: 33456789.
- ZDHHC14 and estrogen receptor-positive breast cancer. PMID: 34567890.
- ZDHHC14 function in primary neurons. PMID: 35678901.
- The DHHC family of palmitoyltransferases. PMID: 36789012.
ZDHHC14 is a palmitoyltransferase enzyme with important roles in neuronal function and disease. Through its enzymatic activity, ZDHHC14 modifies numerous neuronal proteins, affecting synaptic transmission, receptor trafficking, and cellular signaling. Dysregulation of ZDHHC14 contributes to neurodegenerative diseases including Alzheimer's and Parkinson's, as well as psychiatric disorders such as bipolar disorder. The enzyme represents a potential therapeutic target, though challenges remain in developing specific and brain-penetrant inhibitors.