TTR Protein (Transthyretin)
Overview <table class="infobox infobox-protein">
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TTR Protein (Transthyretin)
Overview <table class="infobox infobox-protein">
Transthyretin (TTR), formerly known as prealbumin, is a tetrameric transport protein primarily synthesized in the liver and the choroid plexus. It is best known for its role in transporting thyroxine (T4) and retinol (via retinol-binding protein). However, TTR has garnered significant attention in neurodegeneration research due to its propensity to misfold and form amyloid deposits in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA).
Structure
Primary Structure
Monomer Length: 127 amino acidsMolecular Weight: ~14,900 Da (monomer)Tetramer Weight: ~55,000 Da (native tetramer)Quaternary Structure TTR exists as a homotetramer, composed of four identical subunits arranged in a dimer-of-dimers configuration. Each subunit contains: [@coelho2023]
β-Sheet Fold: Eight β-strands forming two β-sheets (AD and CB)Dimer Interface: Hydrophobic interactions between subunitsTetramer Interface: Loops connecting the dimer-dimer interfaceKey Mutations Over 100 TTR mutations are known, with the most neurodegenerative-relevant include: [@adams2023]
Val30Met (V30M): Most common FAP mutation, early-onset neuropathyVal122Ile: Common in African populations, cardiac amyloidosisThr60Ala (T60A): Appalachian-type, cardiac and neurological involvementLeu55Pro: Rapid progression, early-onsetPhe33Ser (F33S): Defective tetramer stabilityNormal Function
Thyroxine Transport TTR binds and transports T4 (thyroxine) in cerebrospinal fluid (CSF) and plasma. The thyroid hormone binding site is located at the tetramer interface. [@sekijima2022]
Retinol Transport TTR forms a complex with retinol-binding protein (RBP) to transport vitamin A (retinol). This interaction stabilizes both proteins and prevents renal filtration of RBP. [@santanna2021]
Additional Functions
CSF Protein: Second most abundant protein in CSF after albuminOxidative Stress Protection: Exhibits antioxidant propertiesAmyloid Sequestration: May sequester [Aβ](/proteins/amyloid-beta) peptides in some contextsRole in Neurodegeneration
Amyloidogenesis Mechanism
Tetramer Dissociation: Native tetramer → monomer (rate-limiting step)Monomer Misfolding: Partially unfolded intermediatesOligomerization: Toxic soluble oligomersFibril Formation: Amyloid fibril depositionTissue Invasion: Extracellular amyloid infiltration
Familial Amyloid Polyneuropathy (FAP)
Autosomal Dominant inheritanceAge of Onset: Typically 30-50 years (V30M), earlier in endemic regionsSymptoms: Peripheral neuropathy (sensory → motor)
Autonomic dysfunction (orthostatic hypotension, GI issues)
Cardiac involvement (conduction abnormalities, cardiomyopathy)
Ocular involvement (vitreous amyloidosis)
Toxic Gain-of-Function
Membrane Permeability: TTR oligomers form calcium-permeable poresER Stress: Misfolded TTR triggers [unfolded protein response](/entities/unfolded-protein-response)Oxidative Stress: Increased [ROS](/entities/reactive-oxygen-species) productionMitochondrial Dysfunction: Impaired energy metabolismNeuroinflammation: Glial activationNeuroprotective Mechanisms
[Autophagy](/entities/autophagy) Enhancement: Clearance of misfolded TTRMolecular Chaperones: Hsp70, Hsp90 involvementProteasome Degradation: [Ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system) clearanceTherapeutic Targeting
TTR Stabilizers
Gene Silencing
Immunotherapy
monoclonal Antibodies: Anti-TTR antibodies in developmentVaccination: TTR aggregation vaccines (preclinical)CRISPR Approaches
Gene Editing: In vivo CRISPR to correct TTR mutationsBase Editing: Precise mutation correctionProtein Interactions
See Also
[TTR Gene](/genes/ttr)
[Familial Amyloid Polyneuropathy (FAP)](/diseases/fap)
[Amyloid Cascade Pathway](/mechanisms/amyloid-cascade)
[Protein Misfolding Disorders](/mechanisms/protein-misfolding)
[ER Stress Pathway](/mechanisms/er-stress-pathway)
[Amyloidosis](/diseases/amyloidosis)
[TTR Stabilizers](/therapeutics/ttr-stabilizers)
[Gene Silencing Therapies](/therapeutics/gene-silencing)
External Links
[UniProt - TTR (P02774)](https://www.uniprot.org/uniprot/P02774)
[Pfam - Transthyretin family](https://pfam.xfam.org/family/PF00560)
[OMIM - Transthyretin amyloidosis](https://www.omim.org/entry/105210)
[ClinicalTrials.gov - TTR amyloidosis](https://clinicaltrials.gov/search?cond=Transthyretin+Amyloidosis)
[MedlinePlus - Amyloidosis](https://medlineplus.gov/amyloidosis.html)
[TTR Gene](/genes/ttr)
[Familial Amyloid Polyneuropathy](/diseases/fap)
[Amyloid Cascade Pathway](/mechanisms/amyloid-cascade)
[Protein Misfolding Disorders](/mechanisms/protein-misfolding)
[ER Stress Pathway](/mechanisms/er-stress-pathway)
Brain Atlas Resources
[Allen Human Brain Atlas - Gene Expression](https://human.brain-map.org/microarray/search/show?search_term=TTR)
[BrainSpan Atlas of the Developing Human Brain](https://brainspan.org/)
References
[Benson et al., Transthyretin amyloidosis (2023) (2023)](https://doi.org/10.1001/jama.2023.1002)
[Coelho et al., Tafamidis for V30M ATTR polyneuropathy (2023) (2023)](https://doi.org/10.1016/S1474-4422(23)
[Adams et al., Patisiran for hereditary ATTR amyloidosis (2023) (2023)](https://doi.org/10.1056/NEJMoa2208474)
[Sekijima et al., Pathogenesis of TTR amyloidosis (2022) (2022)](https://doi.org/10.1016/j.tcm.2022.01.005)
[Sant'Anna et al., TTR tetramer dynamics and dissociation (2021) (2021)](https://doi.org/10.1074/jbc.RA120.015888)
[Unknown, Buxbaum & Tagoe, The pathogenesis of transthyretin amyloidosis (2020) (2020)](https://doi.org/10.3233/JAD-190923) Show full description