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- PDB-9zdy: Human TTR-C10A at pH 4 -

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Basic information

Entry
Database: PDB / ID: 9zdy
TitleHuman TTR-C10A at pH 4
ComponentsTransthyretin
KeywordsTRANSPORT PROTEIN / thyroxine transporter
Function / homology
Function and homology information


Defective visual phototransduction due to STRA6 loss of function / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / hormone binding / Non-integrin membrane-ECM interactions / molecular sequestering activity / Retinoid metabolism and transport / retinoid metabolic process / hormone activity / azurophil granule lumen ...Defective visual phototransduction due to STRA6 loss of function / The canonical retinoid cycle in rods (twilight vision) / purine nucleobase metabolic process / hormone binding / Non-integrin membrane-ECM interactions / molecular sequestering activity / Retinoid metabolism and transport / retinoid metabolic process / hormone activity / azurophil granule lumen / Amyloid fiber formation / Neutrophil degranulation / protein-containing complex binding / : / protein-containing complex / extracellular exosome / extracellular region / identical protein binding
Similarity search - Function
Transthyretin, conserved site / Transthyretin signature 2. / Transthyretin, thyroxine binding site / Transthyretin signature 1. / Transthyretin / Transthyretin/hydroxyisourate hydrolase / Transthyretin/hydroxyisourate hydrolase domain / Transthyretin/hydroxyisourate hydrolase domain superfamily / HIUase/Transthyretin family
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsSchaefer, J.H. / Lander, G.C.
Funding support United States, Germany, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS095892 United States
German Research Foundation (DFG)556478029 Germany
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Transthyretin can denature by an alternative pathway.
Authors: Marcus Jäger / Jan-Hannes Schäfer / Gabriel C Lander / Evan T Powers / Martin Gruebele / Jeffery W Kelly /
Abstract: Transthyretin (TTR) is a kinetically stable protein in the bloodstream, cerebrospinal fluid, and in the eye, whose aggregation causes a prominent human amyloid disease, TTR amyloidosis (ATTR). ...Transthyretin (TTR) is a kinetically stable protein in the bloodstream, cerebrospinal fluid, and in the eye, whose aggregation causes a prominent human amyloid disease, TTR amyloidosis (ATTR). Dissociation of the wild-type TTR tetramer into metastable dimers is rate-limiting for aggregation at acidic pH and unfolding in denaturant solutions at neutral pH. However, this "canonical dimer" pathway of denaturation is not the only one accessible under conditions possibly relevant to amyloid disease. At pH-values reached in the late endosome and lysosome (pH 4.0 to 5.0), as well as with perturbing mutations at neutral pH, a second denaturation pathway becomes accessible involving a more expanded transition state. This "alternative unfolding" pathway is evident via a characteristic switch to a steeper slope in the plot of the log-transformed unfolding rate constant vs. the urea concentration. Using mutations, we identify globally distributed locations in the protein that are sensitive to pathway-switching and correlate them with structural information. We show that flux along the alternative denaturation pathway becomes kinetically competitive in a subset of variants under mildly acidic conditions. A small-molecule kinetic stabilizer of TTR decreases flux along the canonical denaturation pathway, and exhibits reduced influence on denaturation by the alternative pathway. We present a "universal" plot allowing classification of TTR mutants to either pathway, and suggest a mechanism by which the two pathways operate. We speculate that the existence of an alternative unfolding pathway could allow for rapid protein degradation and turnover of kinetically stable TTR under acidic conditions in the autolysosome.
History
DepositionNov 26, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transthyretin
B: Transthyretin
C: Transthyretin
D: Transthyretin


Theoretical massNumber of molelcules
Total (without water)58,9504
Polymers58,9504
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transthyretin / ATTR / Prealbumin / TBPA


Mass: 14737.438 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TTR, PALB / Production host: Escherichia coli (E. coli) / References: UniProt: P02766
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TTR homotetramer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS TALOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 487780 / Symmetry type: POINT
RefinementHighest resolution: 3.9 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043672
ELECTRON MICROSCOPYf_angle_d0.7445016
ELECTRON MICROSCOPYf_dihedral_angle_d6.895499
ELECTRON MICROSCOPYf_chiral_restr0.054571
ELECTRON MICROSCOPYf_plane_restr0.005642

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