+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-19395 | |||||||||
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Title | CryoEM structure of recombinant human Bri2 BRICHOS oligomers | |||||||||
Map data | ||||||||||
Sample |
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Keywords | chaperone / 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Chen G / Johansson J / Hebert H | |||||||||
Funding support | Sweden, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_19395.map.gz | 11.6 MB | EMDB map data format | |
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Header (meta data) | emd-19395-v30.xml emd-19395.xml | 15.4 KB 15.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_19395_fsc.xml | 7.3 KB | Display | FSC data file |
Images | emd_19395.png | 82.9 KB | ||
Filedesc metadata | emd-19395.cif.gz | 5.8 KB | ||
Others | emd_19395_half_map_1.map.gz emd_19395_half_map_2.map.gz | 11.8 MB 11.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-19395 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-19395 | HTTPS FTP |
-Validation report
Summary document | emd_19395_validation.pdf.gz | 644.6 KB | Display | EMDB validaton report |
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Full document | emd_19395_full_validation.pdf.gz | 644.2 KB | Display | |
Data in XML | emd_19395_validation.xml.gz | 11.2 KB | Display | |
Data in CIF | emd_19395_validation.cif.gz | 15.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-19395 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-19395 | HTTPS FTP |
-Related structure data
Related structure data | 8rnuMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_19395.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_19395_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_19395_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Recombinant human Bri2 BRICHOS oligomers
Entire | Name: Recombinant human Bri2 BRICHOS oligomers |
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Components |
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-Supramolecule #1: Recombinant human Bri2 BRICHOS oligomers
Supramolecule | Name: Recombinant human Bri2 BRICHOS oligomers / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 205 KDa |
-Macromolecule #1: Integral membrane protein 2B
Macromolecule | Name: Integral membrane protein 2B / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 13.949985 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: QTIEENIKIF EEEEVEFISV PVPEFADSDP ANIVHDFNKK LTAYLDLNLD KCYVIPLNTS IVMPPRNLLE LLINIKAGTY LPQSYLIHE HMVITDRIEN IDHLGFFIYR LCHDKETYKL UniProtKB: Integral membrane protein 2B |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.08 mg/mL |
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Buffer | pH: 8 |
Grid | Model: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Support film - Material: GRAPHENE / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 288 K / Instrument: FEI VITROBOT MARK II |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film 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 beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
+Image processing
-Atomic model buiding 1
Initial model | Chain - Source name: AlphaFold / Chain - Initial model type: in silico model |
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Refinement | Space: REAL / Protocol: FLEXIBLE FIT / Overall B value: 420 |
Output model | PDB-8rnu: |