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- EMDB-19395: CryoEM structure of recombinant human Bri2 BRICHOS oligomers -

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Basic information

Entry
Database: EMDB / ID: EMD-19395
TitleCryoEM structure of recombinant human Bri2 BRICHOS oligomers
Map data
Sample
  • Complex: Recombinant human Bri2 BRICHOS oligomers
    • Protein or peptide: Integral membrane protein 2B
Keywordschaperone / anti-amyloid / dementia / Bri2
Function / homology
Function and homology information


negative regulation of amyloid precursor protein biosynthetic process / Golgi-associated vesicle membrane / organelle membrane / nervous system development / amyloid-beta binding / endosome membrane / Amyloid fiber formation / Golgi membrane / intracellular membrane-bounded organelle / Golgi apparatus ...negative regulation of amyloid precursor protein biosynthetic process / Golgi-associated vesicle membrane / organelle membrane / nervous system development / amyloid-beta binding / endosome membrane / Amyloid fiber formation / Golgi membrane / intracellular membrane-bounded organelle / Golgi apparatus / extracellular space / extracellular exosome / extracellular region / ATP binding / membrane / plasma membrane
Similarity search - Function
Integral membrane protein 2 / BRICHOS / BRICHOS domain / BRICHOS domain / BRICHOS domain profile.
Similarity search - Domain/homology
Integral membrane protein 2B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChen G / Johansson J / Hebert H
Funding support Sweden, 1 items
OrganizationGrant numberCountry
Swedish Research Council Sweden
CitationJournal: Protein Sci / Year: 2024
Title: Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain.
Authors: Gefei Chen / Yu Wang / Zihan Zheng / Wangshu Jiang / Axel Leppert / Xueying Zhong / Anna Belorusova / Gregg Siegal / Caroline Jegerschöld / Philip J B Koeck / Axel Abelein / Hans Hebert / ...Authors: Gefei Chen / Yu Wang / Zihan Zheng / Wangshu Jiang / Axel Leppert / Xueying Zhong / Anna Belorusova / Gregg Siegal / Caroline Jegerschöld / Philip J B Koeck / Axel Abelein / Hans Hebert / Stefan D Knight / Jan Johansson /
Abstract: Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several ...Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein. High-confidence AlphaFold2 and RoseTTAFold predictions suggest that the intramolecular amyloidogenic region (Bri23) is part of the hydrophobic core of the proprotein, where it occupies the proposed amyloid binding site, explaining the markedly reduced ability of the proprotein to prevent an exogenous amyloidogenic peptide from aggregating. However, the BRICHOS-Bri23 complex maintains its ability to form large polydisperse oligomers that prevent amorphous protein aggregation. A cryo-EM-derived model of the Bri2 BRICHOS oligomer is compatible with surface-exposed hydrophobic motifs that get exposed and come together during oligomerization, explaining its effects against amorphous aggregation. These findings provide a molecular basis for the BRICHOS chaperone domain function, where distinct surfaces are employed against different forms of protein aggregation.
History
DepositionJan 11, 2024-
Header (metadata) releaseJun 19, 2024-
Map releaseJun 19, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_19395.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 160 pix.
= 169.6 Å
1.06 Å/pix.
x 160 pix.
= 169.6 Å
1.06 Å/pix.
x 160 pix.
= 169.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.008
Minimum - Maximum-0.0061491304 - 0.049778506
Average (Standard dev.)0.0009589252 (±0.0026231527)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 169.59999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_19395_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_19395_half_map_2.map
Projections & Slices
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Sample components

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Entire : Recombinant human Bri2 BRICHOS oligomers

EntireName: Recombinant human Bri2 BRICHOS oligomers
Components
  • Complex: Recombinant human Bri2 BRICHOS oligomers
    • Protein or peptide: Integral membrane protein 2B

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Supramolecule #1: Recombinant human Bri2 BRICHOS oligomers

SupramoleculeName: Recombinant human Bri2 BRICHOS oligomers / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 205 KDa

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Macromolecule #1: Integral membrane protein 2B

MacromoleculeName: Integral membrane protein 2B / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.949985 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QTIEENIKIF EEEEVEFISV PVPEFADSDP ANIVHDFNKK LTAYLDLNLD KCYVIPLNTS IVMPPRNLLE LLINIKAGTY LPQSYLIHE HMVITDRIEN IDHLGFFIYR LCHDKETYKL

UniProtKB: Integral membrane protein 2B

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.08 mg/mL
BufferpH: 8
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Support film - Material: GRAPHENE / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 288 K / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 8.0 sec. / Average electron dose: 44.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 589803
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: D3 (2x3 fold dihedral) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 146177
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 420
Output model

PDB-8rnu:
CryoEM structure of recombinant human Bri2 BRICHOS oligomers

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