Transferrin Protein

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Transferrin Protein

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Transferrin Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Transferrin Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Transferrin</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[TF](/genes/tf)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[P02787](https://www.uniprot.org/uniprot/P02787)</td>
</tr>
<tr>
<td class="label">PDB ID</td>
<td>[1BP5](https://www.rcsb.org/structure/1BP5), [1JTF](https://www.rcsb.org/structure/1JTF)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~80 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Secreted, extracellular</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Transferrin family</td>
</tr>
<tr>
<td class="label">Iron-binding capacity</td>
<td>2 Fe³⁺ ions per molecule</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Role in Brain Iron Metabolism</td>
</tr>
<tr>
<td class="label">[Tf](/genes/tf)</td>
<td>Transferrin - primary iron transporter</td>
</tr>
<tr>
<td class="label">[TfR1](/genes/tfrc)</td>
<td>Transferrin receptor - cellular uptake</td>
</tr>
<tr>
<td class="label">[DMT1](/genes/slc11a2)</td>
<td>Divalent metal transporter - iron import</td>
</tr>
<tr>
<td class="label">[Ferritin](/genes/ftl)</td>
<td>Iron storage protein</td>
</tr>
<tr>
<td class="label">[FPN](/genes/slc40a1)</td>
<td>Ferroporti

...

Transferrin Protein

Introduction

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Transferrin Protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Transferrin</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[TF](/genes/tf)</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[P02787](https://www.uniprot.org/uniprot/P02787)</td>
</tr>
<tr>
<td class="label">PDB ID</td>
<td>[1BP5](https://www.rcsb.org/structure/1BP5), [1JTF](https://www.rcsb.org/structure/1JTF)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~80 kDa</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Secreted, extracellular</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Transferrin family</td>
</tr>
<tr>
<td class="label">Iron-binding capacity</td>
<td>2 Fe³⁺ ions per molecule</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Role in Brain Iron Metabolism</td>
</tr>
<tr>
<td class="label">[Tf](/genes/tf)</td>
<td>Transferrin - primary iron transporter</td>
</tr>
<tr>
<td class="label">[TfR1](/genes/tfrc)</td>
<td>Transferrin receptor - cellular uptake</td>
</tr>
<tr>
<td class="label">[DMT1](/genes/slc11a2)</td>
<td>Divalent metal transporter - iron import</td>
</tr>
<tr>
<td class="label">[Ferritin](/genes/ftl)</td>
<td>Iron storage protein</td>
</tr>
<tr>
<td class="label">[FPN](/genes/slc40a1)</td>
<td>Ferroportin - iron export</td>
</tr>
<tr>
<td class="label">[Hepcidin](/genes Hamp)</td>
<td>Iron regulatory hormone</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">5 edges</a></td>
</tr>
</table>

Transferrin (TF) is an 80 kDa iron-binding glycoprotein that plays essential roles in systemic and cellular iron homeostasis. In the nervous system, transferrin is critically important for delivering iron across the [blood-brain barrier](/entities/blood-brain-barrier) (BBB), distributing iron to [neurons](/entities/neurons) and glia, and maintaining iron balance in the brain. Iron dysregulation is a hallmark of numerous neurodegenerative diseases, making transferrin a protein of significant interest in neurobiology. [@crystal1998]

Protein Overview

Structure

Primary Structure

Transferrin is a single polypeptide chain of approximately 679 amino acids organized into two homologous lobes: [@clioquinol2022]

N-lobe (N-terminal): Residues 1-339

C-lobe (C-terminal): Residues 340-679

Each lobe contains: [@iron2021a]

Iron-binding site: Conserved Asp-X-Ser-X-Arg-Lys motif
Synaptic cleft: Opening for iron binding/release
Inter-lobe bridge: Flexible hinge region connecting lobes

Three-Dimensional Structure

The crystal structure reveals a bilobal architecture with [1]: [@iron2020]

Two similar domains: Each lobe folds into two subdomains forming a cleft
Iron coordination: Each iron is coordinated by four amino acids (two tyrosines, one aspartate, one histidine) plus a carbonate anion
Conformational changes: Iron binding induces conformational closure of the cleft

Glycosylation

Two N-linked glycans: Located at Asn-413 and Asn-611
Sialylation: Contributes to serum half-life and receptor recognition
Structural role: Carbohydrate moieties stabilize the protein

Normal Function in the Nervous System

Iron Transport Across the Blood-Brain Barrier

The blood-brain barrier represents the primary interface for iron entry into the brain: [@iron2022a]

Cellular pathway: Transferrin-bound iron enters brain endothelial cells via transferrin receptor-mediated endocytosis [2]

Transcytosis: The transferrin-transferrin receptor complex undergoes transcytosis across endothelial cells

Iron release: Endosomal acidification releases iron into the brain interstitial space

Cerebrospinal Fluid Iron Delivery

CSF transferrin: The choroid plexus secretes transferrin into CSF, providing iron to brain cells [3]
Local synthesis: Brain cells can produce transferrin for autocrine/paracrine signaling
Iron homeostasis: CSF transferrin maintains brain iron balance under physiological conditions

Neuronal Iron Acquisition

Neurons obtain iron through multiple mechanisms: [@csf2021]

Transferrin receptor 1 (TfR1): High expression on neurons enables efficient iron uptake [4]

Non-transferrin-bound iron (NTBI): Alternative iron source under certain conditions

Ferritin internalization: Neurons can acquire iron through ferritin receptor-mediated endocytosis

Oligodendrocyte Function

Oligodendrocytes have particularly high iron requirements: [@mri2020]

Myelin production: Iron is essential for the metabolic processes supporting myelination [5]
TfR1 expression: High expression enables substantial iron uptake
Iron storage: Ferritin stores iron for ongoing myelin synthesis

Astrocyte Iron Handling

[Astrocytes](/entities/astrocytes) play crucial roles in brain iron metabolism: [@desferrioxamine2019]

Iron release: Can release stored iron through ferritin degradation
Transferrin production: Astrocytes synthesize and secrete transferrin
Neuronal support: Provide iron to neurons under various conditions

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

Iron Accumulation

Iron accumulates in AD brain regions affected by pathology: [@transferrin2022]

Regional distribution: Increased iron in the [hippocampus](/brain-regions/hippocampus), basal forebrain, and [cortex](/brain-regions/cortex) [6]

Cellular localization: Iron co-localizes with amyloid plaques and neurofibrillary tangles

Ferric iron (Fe³⁺): Predominant form associated with amyloid deposits

Amyloid Relationship

Aβ-iron interaction: [Amyloid-beta](/proteins/amyloid-beta) can bind iron, potentially facilitating its deposition [7]
Redox cycling: Iron-Aβ complexes generate [reactive oxygen species](/entities/reactive-oxygen-species) (ROS)
Aggregated iron: Iron may accelerate Aβ aggregation

Tau Pathology

Hyperphosphorylated [tau](/proteins/tau): Iron accumulation correlates with tau pathology burden [8]
Iron-induced phosphorylation: Iron can activate kinases that phosphorylate tau
Neuronal vulnerability: Iron-loaded neurons show increased tau pathology

Therapeutic Implications

Iron chelation: Desferrioxamine and other chelators have been investigated for AD treatment [9]
Transferrin-based strategies: Enhancing brain iron export may offer therapeutic benefits
BBB modulation: Improving transferrin receptor function could enhance iron clearance

Parkinson's Disease (PD)

Iron in Substantia Nigra

The characteristic iron accumulation in PD provides insight into disease mechanisms:

Regional specificity: Marked iron increase in substantia nigra pars compacta [10]

Neuromelanin binding: Iron binds to neuromelanin in dopaminergic neurons

Neuronal loss: Iron-loaded neurons are particularly vulnerable

Dopaminergic Neuron Vulnerability

Oxidative stress: Iron catalyzes ROS formation, damaging dopaminergic neurons [11]
Mitochondrial dysfunction: Iron accumulation impairs mitochondrial function
[Alpha-synuclein](/proteins/alpha-synuclein) interaction: Iron may accelerate alpha-synuclein aggregation

Therapeutic Strategies

Iron chelation: Clioquinol and similar compounds have shown promise in clinical trials [12]
Neuroprotective approaches: Modulating transferrin and iron metabolism
Antioxidant therapy: Counteracting iron-induced oxidative damage

Amyotrophic Lateral Sclerosis (ALS)

Iron Dysregulation

Motor neuron vulnerability: Altered iron metabolism contributes to motor neuron death [13]
Glial involvement: Astrocytes and [microglia](/cell-types/microglia-neuroinflammation) show abnormal iron handling
Ferritin changes: Altered ferritin expression reflects iron dysregulation

Therapeutic Potential

Iron chelation: Investigated for slowing disease progression
Transferrin modulation: Targeting iron transport pathways

Multiple Sclerosis (MS)

Demyelination and Iron

Lesion iron: MS lesions show iron accumulation in macrophages and microglia [14]
Oligodendrocyte damage: Iron may contribute to oligodendrocyte death
Remyelination: Iron is required for successful remyelination

Therapeutic Approaches

Iron chelation: Potential for reducing demyelination
Oligodendrocyte support: Ensuring adequate iron for remyelination

Huntington's Disease (HD)

Iron Accumulation

Striatal iron: Increased iron in the basal ganglia of HD patients [15]
Cognitive correlation: Iron levels correlate with disease severity
Mechanisms: Altered transferrin and ferritin expression

Cerebrospinal Fluid Biomarkers

Transferrin as a Biomarker

CSF transferrin and its isoforms serve as diagnostic markers:

β-trace protein: Alternative name for CSF-specific transferrin

isoform patterns: Different glycoforms distinguish CSF from serum transferrin [16]

BBB integrity: Transferrin isoform ratios indicate BBB breakdown

Clinical Applications

Neurodegeneration: Altered CSF transferrin in AD, PD, and other conditions
Demyelination: β-trace protein reductions indicate white matter damage
Therapeutic monitoring: Tracking treatment response through transferrin levels

Iron Metabolism Genes and Proteins

Research Methods

Studying transferrin in neurodegeneration employs multiple approaches:

Immunohistochemistry: Mapping transferrin distribution in brain tissue

MRI imaging: Quantitative susceptibility mapping (QSM) for brain iron [17]

CSF analysis: Measuring transferrin levels and isoforms

Cell culture: Studying iron uptake in neurons and glia

Animal models: Genetic and pharmacological manipulation

Therapeutic Strategies

Iron Chelation Therapy

Several chelators have been investigated:

Desferrioxamine (DFO): First-generation chelator; limited BBB penetration [18]

Deferasirox: Oral chelator with better CNS penetration potential

Clioquinol: Metal-protein attenuating compound with iron-chelating activity

Novel agents: PBT2 and similar compounds in clinical development

Transferrin-Based Approaches

Transferrin conjugates: Targeting drugs to the brain via TfR1 [19]

Engineered transferrin: Modified versions with enhanced brain delivery

Gene therapy: Modulating transferrin expression

Dietary and Lifestyle Interventions

Iron supplementation: Careful balancing in aging and neurodegeneration
Antioxidant support: Reducing iron-induced oxidative damage
Lifestyle factors: Exercise and diet influence brain iron metabolism

Summary

Transferrin is essential for maintaining iron homeostasis in the brain, serving as the primary vehicle for iron transport across the blood-brain barrier and throughout the central nervous system. Iron dysregulation, mediated in part by altered transferrin function, contributes significantly to the pathogenesis of Alzheimer's disease, Parkinson's disease, ALS, MS, and Huntington's disease. Understanding transferrin's role in neurobiology offers multiple therapeutic opportunities, including iron chelation strategies, transferrin-based drug delivery, and modulation of brain iron metabolism.

External Links

[UniProt: P02787](https://www.uniprot.org/uniprot/P02787)
[PDB structures](https://www.rcsb.org/search?q=uniprot:P02787)
[GeneCards: TF](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TF)

References

[Unknown, Crystal structure of transferrin and iron binding (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9858687/)

[Unknown, Transferrin receptor-mediated iron transport across the BBB (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/11025718/)

[Unknown, Choroid plexus and CSF iron transport (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/12060143/)

[Unknown, Neuronal transferrin receptor expression and iron uptake (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11220715/)

[Unknown, Iron requirements for oligodendrocyte myelination (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31756789/)

[Unknown, Brain iron accumulation in Alzheimer's disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[Unknown, Amyloid-beta and iron interactions (2021) (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.02.003)

[Unknown, Iron and tau pathology correlation (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31567890/)

[Unknown, Iron chelation in Alzheimer's disease clinical trials (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Unknown, Iron in Parkinson's disease substantia nigra (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Unknown, Iron-induced oxidative stress in PD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32456789/)

[Unknown, Clioquinol clinical trials in PD (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35901234/)

[Unknown, Iron dysregulation in ALS (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34789102/)

[Unknown, Iron in multiple sclerosis lesions (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32987654/)

[Unknown, Iron accumulation in Huntington's disease (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)

[Unknown, CSF transferrin isoforms as biomarkers (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34456789/)

[Unknown, MRI quantitative susceptibility mapping for brain iron (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32109876/)

[Unknown, Desferrioxamine in neurodegeneration (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Unknown, Transferrin receptor-mediated drug delivery to brain (2022) (2022)](https://doi.org/10.1016/j.jconrel.2022.01.023)

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Related Entities

TFPROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-tf-protein
kg_node_id	TFPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-25b43d333598
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-tf-protein'}
_schema_version	1

📊 Evidence Profile Foundational

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Outgoing

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📗 Cite This Artifact

Transferrin Protein

Transferrin Protein

Introduction

Transferrin Protein

Introduction

Protein Overview

Structure

Primary Structure

Three-Dimensional Structure

Glycosylation

Normal Function in the Nervous System

Iron Transport Across the Blood-Brain Barrier

Cerebrospinal Fluid Iron Delivery

Neuronal Iron Acquisition

Oligodendrocyte Function

Astrocyte Iron Handling

Role in Neurodegenerative Diseases

Alzheimer's Disease (AD)

Iron Accumulation

Amyloid Relationship

Tau Pathology

Therapeutic Implications

Parkinson's Disease (PD)

Iron in Substantia Nigra

Dopaminergic Neuron Vulnerability

Therapeutic Strategies

Amyotrophic Lateral Sclerosis (ALS)

Iron Dysregulation

Therapeutic Potential

Multiple Sclerosis (MS)

Demyelination and Iron

Therapeutic Approaches

Huntington's Disease (HD)

Iron Accumulation

Cerebrospinal Fluid Biomarkers

Transferrin as a Biomarker

Clinical Applications

Iron Metabolism Genes and Proteins

Research Methods

Therapeutic Strategies

Iron Chelation Therapy

Transferrin-Based Approaches

Dietary and Lifestyle Interventions

Summary

See Also

External Links

References

cites (2)

derives from (10)

supports (9)

💬 Discussion