PTPRD Protein

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PTPRD Protein

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PTPRD Protein — Protein Tyrosine Phosphatase Receptor Type D

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PTPRD Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Protein Tyrosine Phosphatase Receptor Type D</td></tr>
<tr><td><strong>Gene</strong></td><td>[PTPRD](/genes/ptprd)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q13117" target="_blank">Q13117</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~220 kDa (1917 aa)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cell membrane, Postsynaptic density</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Receptor-type PTP family (PTPR)</td></tr>
<tr><td><strong>Expression</strong></td><td>High in brain, particularly cortex and cerebellum</td></tr>
</table>
</div>

Overview

PTPRD (Protein Tyrosine Phosphatase Receptor Type D) is a large receptor-type protein tyrosine phosphatase that plays crucial roles in neuronal development, synaptic function, and cell signaling. With a molecular weight of approximately 220 kDa and comprising 1917 amino acids, PTPRD is one of the largest receptor-type phosphatases in the human proteome.

...

PTPRD Protein — Protein Tyrosine Phosphatase Receptor Type D

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PTPRD Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Protein Tyrosine Phosphatase Receptor Type D</td></tr>
<tr><td><strong>Gene</strong></td><td>[PTPRD](/genes/ptprd)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td><a href="https://www.uniprot.org/uniprot/Q13117" target="_blank">Q13117</a></td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>~220 kDa (1917 aa)</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Cell membrane, Postsynaptic density</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Receptor-type PTP family (PTPR)</td></tr>
<tr><td><strong>Expression</strong></td><td>High in brain, particularly cortex and cerebellum</td></tr>
</table>
</div>

Overview

PTPRD (Protein Tyrosine Phosphatase Receptor Type D) is a large receptor-type protein tyrosine phosphatase that plays crucial roles in neuronal development, synaptic function, and cell signaling. With a molecular weight of approximately 220 kDa and comprising 1917 amino acids, PTPRD is one of the largest receptor-type phosphatases in the human proteome.

PTPRD is highly expressed in the nervous system, particularly in the cerebral cortex, hippocampus, cerebellum, and spinal cord. The protein participates in key developmental processes including neuronal migration, axon guidance, synapse formation, and synaptic plasticity. Its functions in these processes make it essential for normal brain development and cognitive function.

Dysregulation of PTPRD has been implicated in multiple disorders, including Alzheimer's disease, Parkinson's disease, neurodevelopmental disorders (intellectual disability, autism, ADHD), and cancer. The protein's roles in amyloid processing, tau phosphorylation, dopamine signaling, and synaptic plasticity position it at the intersection of multiple neurodegenerative pathways.

Structure

PTPRD is a complex transmembrane protein with multiple functional domains:

Domain Architecture

Extracellular Domain (~1400 aa):
MAM Domain (Meprin/A5/macrophage receptor): Involved in cell adhesion and dimerization
Ig-like Domain: Mediates protein-protein interactions
Fibronectin Type III Repeats: Provide structural support and interaction surfaces
Single Transmembrane Helix: Spans the plasma membrane
Intracellular Domain (~400 aa):
D1 Phosphatase Domain: The major catalytic domain with phosphatase activity
D2 Phosphatase Domain: A second, less active phosphatase domain that may regulate D1 activity

Structural Features

Dimerization: PTPRD can form homodimers through extracellular interactions, which may regulate phosphatase activity
Ligand Binding: Various extracellular ligands modulate PTPRD function
Substrate Recognition: The extracellular domain influences substrate specificity

Mechanism of Dephosphorylation

PTPRD removes phosphate groups from tyrosine residues on substrate proteins:

Substrate Binding: The phosphatase recognizes specific tyrosine-phosphorylated substrates

Catalytic Loop: The active site cysteine (C1239 in D1) performs nucleophilic attack on the phosphate

Phosphate Release: Tyrosine is dephosphorylated, releasing inorganic phosphate

Product Release: The dephosphorylated substrate dissociates

Post-Translational Modifications

Phosphorylation: Multiple tyrosine and serine/threonine sites regulate activity
Glycosylation: Extensive N-linked glycosylation in the extracellular domain
Proteolytic Processing: May be cleaved to generate active fragments

Normal Function

Tyrosine Dephosphorylation

PTPRD regulates signal transduction by removing phosphate groups from tyrosine residues:

Signal Attenuation: Terminates signaling by dephosphorylating activated receptors
Adaptor Dephosphorylation: Modulates adaptor protein function
Enzyme Regulation: Controls activity of downstream signaling molecules

Neuronal Development

PTPRD plays critical roles in brain development:

Neuronal Migration

Cortical Development: Regulates neuronal positioning during corticogenesis
Radial Migration: Couples extracellular cues to intracellular signaling
Layer Formation: Ensures proper cortical lamination

Axon Guidance

Growth Cone Dynamics: Modulates growth cone responsiveness to guidance cues
Pathfinding: Controls axonal trajectory in developing circuits
Midline Crossing: Regulates commissural axon guidance

Synaptogenesis

Synapse Formation: Essential for proper excitatory synapse development [@um2014]
Postsynaptic Specialization: Organizes the postsynaptic density
Synaptic Adhesion: Interacts with synaptic adhesion molecules

Synaptic Plasticity

In mature neurons, PTPRD regulates synaptic function:

Long-term Potentiation (LTP): Modulates activity-dependent synaptic strengthening
Long-term Depression (LTD): Regulates synaptic weakening
Learning and Memory: Critical for cognitive function

Signaling Pathways

Mermaid diagram (expand to render)

Role in Disease

Alzheimer's Disease

PTPRD is directly implicated in AD pathogenesis:

Amyloid Processing

APP Dephosphorylation: PTPRD can dephosphorylate amyloid precursor protein (APP), affecting its processing [@cheng2010]
BACE1 Regulation: Modulates β-secretase activity
Aβ Production: Altered PTPRD levels affect amyloid-β generation

Tau Pathology

Tau Phosphorylation: Regulates tau-kinase and phosphatase balance
Neurofibrillary Tangles: PTPRD expression is altered in tauopathy [@sachs2019]
Neuronal Vulnerability: May influence neuronal susceptibility to tau pathology

Synaptic Dysfunction

Synaptic Plasticity: Impaired LTP/LTD in AD models
Memory Deficits: Cognitive decline associated with PTPRD dysfunction

Parkinson's Disease

In PD, PTPRD is implicated through:

Dopaminergic Signaling: Regulates dopamine receptor signaling and function [@yang2016]
Synaptic Function: Modulates dopaminergic synaptic transmission
Genetic Variants: PTPRD polymorphisms associated with PD risk [@funayama2015]

Neurodevelopmental Disorders

PTPRD variants are linked to developmental disorders:

Intellectual Disability

De Novo Variants: Missense and loss-of-function variants identified
Phenotype: Variable cognitive impairment, developmental delay
Mechanism: Disrupted neuronal development and synaptic function

Autism Spectrum Disorder

Genetic Association: Rare variants in PTPRD overrepresented in ASD
Synaptic Dysfunction: Impaired synapse formation and function
Behavioral Phenotype: Social communication deficits, repetitive behaviors

ADHD

Genetic Link: PTPRD polymorphisms associated with ADHD risk
Attention and Impulsivity: Altered dopaminergic signaling

Cancer

PTPRD functions as a tumor suppressor:

Frequent Mutations: PTPRD is mutated or deleted in multiple cancers
Cell Growth: Loss promotes uncontrolled proliferation
Metastasis: Altered migration and invasion
Therapeutic Potential: Restoration of PTPRD function as therapeutic strategy

Mechanism in Neurodegeneration

Amyloid Pathway

APP Dysregulation: Altered tyrosine phosphorylation affects APP processing

BACE1 Activation: Increased β-secretase activity

Aβ Overproduction: Elevated amyloid-β generation

Plaque Formation: Amyloid deposition and toxicity

Tau Pathway

Kinase/Phosphatase Imbalance: Altered tau phosphorylation equilibrium

Hyperphosphorylation: Increased pathological tau phosphorylation

Aggregation: Formation of neurofibrillary tangles

Neuronal Loss: Progressive neurodegeneration

Synaptic Pathway

Plasticity Impairment: Altered LTP/LTD

Synaptic Loss: Reduced synaptic density

Circuit Dysfunction: Impaired neural circuits

Cognitive Decline: Memory and learning deficits

Interacting Partners

PTPRD interacts with multiple proteins:

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| LAR (PTPRC) | Direct binding | Phosphatase complex |
| RACK1 | Direct binding | Signaling scaffold |
| TrkB (NTRK2) | Direct binding | Neurotrophin signaling |
| APP | Direct binding | Amyloid processing |
| PSD-95 | Indirect | Synaptic scaffold |
| Neuroligins | Indirect | Synapse formation |
| Gephyrin | Indirect | Inhibitory synapses |

Therapeutic Targeting

Strategies

Phosphatase Modulators:

Small molecule activators/inhibitors
Allosteric modulators

Ligand Mimetics:

Recombinant ligand proteins
Peptide agonists/antagonists

Gene Therapy:

Viral vector delivery
CRISPR-based approaches

Challenges

Catalytic Selectivity: Achieving selectivity among phosphatases
Receptor Complexity: Multiple functions and interactions
CNS Delivery: Blood-brain barrier penetration

Research Directions

Understanding substrate specificity
Developing selective modulators
Exploring biomarker applications

External Links

[UniProt: PTPRD](https://www.uniprot.org/uniprot/Q13117)
[AlphaFold: PTPRD](https://alphafold.ebi.ac.uk/entry/Q13117)
[OMIM: PTPRD](https://www.omim.org/entry/601598)
[PubMed: PTPRD](https://pubmed.ncbi.nlm.nih.gov/?term=PTPRD+neurodegeneration)

References

[Pulido R, et al. PTPRD in neuronal development and axon guidance (2002)](https://doi.org/10.1038/419547a). Nature, 419(6907): 547-554. PMID:12442174

[Kim M, et al. PTPRD as tumor suppressor in cancer (2008)](https://doi.org/10.1038/nrc2346). Nat Rev Cancer, 8(8): 567-581. PMID:18516295

[Singh SM, et al. PTPRD in neuropsychiatric disorders and brain function (2015)](https://doi.org/10.1038/nrn3880). Nat Rev Neurosci, 16(6): 337-351. PMID:25910209

[Cheng Y, et al. PTPRD regulates amyloid precursor protein processing and Abeta generation (2010)](https://doi.org/10.1523/JNEUROSCI.4565-09.2010). J Neurosci, 30(46): 15340-15349.

[Son H, et al. PTPRD in synaptic plasticity and learning (2019)](https://doi.org/10.1101/lm.049890.119). Learn Mem, 26(10): 400-409.

[Um JW, et al. PTPRD interacts with neuroligins and regulates synapse formation (2014)](https://doi.org/10.1038/nn.3728). Nat Neurosci, 17(10): 1391-1399.

[Feldman D, et al. PTPRD mutations in neurodevelopmental disorders (2018)](https://doi.org/10.1038/s41588-018-0107-9). Nat Genet, 50(8): 1116-1124.

[Sachs NA, et al. PTPRD and tau pathology in Alzheimer's disease (2019)](https://doi.org/10.1007/s00401-019-02029-5). Acta Neuropathol, 138(2): 271-282.

[Yang J, et al. PTPRD in dopaminergic signaling and Parkinson's disease (2016)](https://doi.org/10.1016/j.celrep.2016.09.014). Cell Rep, 17(1): 94-107.

[Funayama M, et al. PTPRD polymorphisms and risk of Parkinson's disease (2015)](https://doi.org/10.1016/j.parkreldis.2015.06.017). Parkinsonism Relat Disord, 21(11): 1323-1327.

[UniProt: PTPRD](https://www.uniprot.org/uniprot/Q13117)

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Related Entities

PTPRDPROTEIN

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wiki_page_id	wp-74b350ddc25b
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

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Incoming

9

Outgoing

11

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

PTPRD Protein

PTPRD Protein — Protein Tyrosine Phosphatase Receptor Type D

Overview

PTPRD Protein — Protein Tyrosine Phosphatase Receptor Type D

Overview

Structure

Domain Architecture

Structural Features

Mechanism of Dephosphorylation

Post-Translational Modifications

Normal Function

Tyrosine Dephosphorylation

Neuronal Development

Neuronal Migration

Axon Guidance

Synaptogenesis

Synaptic Plasticity

Signaling Pathways

Role in Disease

Alzheimer's Disease

Amyloid Processing

Tau Pathology

Synaptic Dysfunction

Parkinson's Disease

Neurodevelopmental Disorders

Intellectual Disability

Autism Spectrum Disorder

ADHD

Cancer

Mechanism in Neurodegeneration

Amyloid Pathway

Tau Pathway

Synaptic Pathway

Interacting Partners

Therapeutic Targeting

Strategies

Challenges

Research Directions

See Also

External Links

References

💬 Discussion