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- PDB-6ic3: AL amyloid fibril from a lambda 1 light chain -

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Basic information

Entry
Database: PDB / ID: 6ic3
TitleAL amyloid fibril from a lambda 1 light chain
Componentslambda 1 light chain fragment, residues 3-118
KeywordsPROTEIN FIBRIL / amyloid fibril / beta sheet / antibody / heart
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsFritz, G. / Faendrich, M. / Schmidt, M. / Radamaker, L.
CitationJournal: Nat Commun / Year: 2019
Title: Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis.
Authors: Lynn Radamaker / Yin-Hsi Lin / Karthikeyan Annamalai / Stefanie Huhn / Ute Hegenbart / Stefan O Schönland / Günter Fritz / Matthias Schmidt / Marcus Fändrich /
Abstract: Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of ...Amyloid fibrils derived from antibody light chains are key pathogenic agents in systemic AL amyloidosis. They can be deposited in multiple organs but cardiac amyloid is the major risk factor of mortality. Here we report the structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å which we determined using cryo-electron microscopy. The fibril core consists of a 91-residue segment presenting an all-beta fold with ten mutagenic changes compared to the germ line. The conformation differs substantially from natively folded light chains: a rotational switch around the intramolecular disulphide bond being the crucial structural rearrangement underlying fibril formation. Our structure provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.
History
DepositionDec 2, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 3, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]

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Assembly

Deposited unit
A: lambda 1 light chain fragment, residues 3-118
B: lambda 1 light chain fragment, residues 3-118
C: lambda 1 light chain fragment, residues 3-118
D: lambda 1 light chain fragment, residues 3-118
E: lambda 1 light chain fragment, residues 3-118
F: lambda 1 light chain fragment, residues 3-118
G: lambda 1 light chain fragment, residues 3-118
H: lambda 1 light chain fragment, residues 3-118


Theoretical massNumber of molelcules
Total (without water)97,4208
Polymers97,4208
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: scanning transmission electron microscopy, Fibril structures visible using negative stain TEM
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area50810 Å2
ΔGint-167 kcal/mol
Surface area25580 Å2
MethodPISA

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Components

#1: Antibody
lambda 1 light chain fragment, residues 3-118


Mass: 12177.463 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: Heart / Tissue: heart muscle

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Amyloid fibril of an antibody lambda 1 light chain / Type: COMPLEX
Details: Extracted fibrils from the heart of a patient suffering from systemic AL amyloidosis
Entity ID: all / Source: NATURAL
Molecular weightValue: 2.5 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human) / Organ: heart / Tissue: heart muscle
Buffer solutionpH: 7
Buffer componentName: distilled water / Formula: H2O
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Sample in pure water, pH not determined
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3 4C
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 294 K / Details: blotted from the backside for 4 s before plunging

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6 sec. / Electron dose: 32 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 847
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 30 / Used frames/image: 1-30

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
EM software
IDNameVersionCategoryDetails
2SerialEMimage acquisition
4Gctf1.06CTF correction
7Warp8model fittingEM model building module of ARP/wARP was used to trace the desnity and build an initial model
8Coot0.8.9model fittingCoot was used to manually build the model
10RELION2.1.0initial Euler assignment
12RELION2.1.0classification
13RELION2.1.03D reconstruction
20PHENIX1.14.3260model refinementphenix.real_space_refine
Image processingDetails: Motion-corrected and dose-weighted movie frames
CTF correctionDetails: CTF was estimated from the non-dose-weighted micrographs
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 0.58 ° / Axial rise/subunit: 4.81 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 119395
Details: manual selection. Sigma contrast 3, lowpass filter 20 A
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 32677 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingB value: 111.4 / Protocol: OTHER / Space: REAL
Target criteria: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Details: Refinement strategy included global minimization and local grid search and ADP were refined. Secondary structure restraints and NCS were applied during refinement.

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