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Yorodumi- EMDB-21410: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-21410 | |||||||||
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Title | Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils | |||||||||
Map data | ||||||||||
Sample |
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Keywords | hIAPP / type II diabetes / amyloid / PROTEIN FIBRIL | |||||||||
Function / homology | Function and homology information SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / : / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring ...SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMOylation of SUMOylation proteins / SUMO is proteolytically processed / : / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring / SUMOylation of DNA damage response and repair proteins / SUMOylation of RNA binding proteins / amylin receptor signaling pathway / Calcitonin-like ligand receptors / SUMOylation of DNA replication proteins / SUMOylation of chromatin organization proteins / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / ubiquitin-like protein ligase binding / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / protein sumoylation / negative regulation of protein-containing complex assembly / positive regulation of cAMP-mediated signaling / positive regulation of calcium-mediated signaling / bone resorption / sensory perception of pain / osteoclast differentiation / condensed nuclear chromosome / hormone activity / protein tag activity / cell-cell signaling / amyloid-beta binding / G alpha (s) signalling events / positive regulation of MAPK cascade / receptor ligand activity / positive regulation of apoptotic process / Amyloid fiber formation / signaling receptor binding / lipid binding / apoptotic process / signal transduction / extracellular space / extracellular region / identical protein binding / nucleus Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | helical reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Cao Q / Boyer DR | |||||||||
Funding support | United States, 1 items
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Citation | Journal: Nat Struct Mol Biol / Year: 2020 Title: Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils. Authors: Qin Cao / David R Boyer / Michael R Sawaya / Peng Ge / David S Eisenberg / Abstract: Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM ...Human islet amyloid polypeptide (hIAPP) functions as a glucose-regulating hormone but deposits as amyloid fibrils in more than 90% of patients with type II diabetes (T2D). Here we report the cryo-EM structure of recombinant full-length hIAPP fibrils. The fibril is composed of two symmetrically related protofilaments with ordered residues 14-37. Our hIAPP fibril structure (i) supports the previous hypothesis that residues 20-29 constitute the core of the hIAPP amyloid; (ii) suggests a molecular mechanism for the action of the hIAPP hereditary mutation S20G; (iii) explains why the six residue substitutions in rodent IAPP prevent aggregation; and (iv) suggests regions responsible for the observed hIAPP cross-seeding with β-amyloid. Furthermore, we performed structure-based inhibitor design to generate potential hIAPP aggregation inhibitors. Four of the designed peptides delay hIAPP aggregation in vitro, providing a starting point for the development of T2D therapeutics and proof of concept that the capping strategy can be used on full-length cryo-EM fibril structures. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21410.map.gz | 7.4 MB | EMDB map data format | |
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Header (meta data) | emd-21410-v30.xml emd-21410.xml | 9.8 KB 9.8 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_21410_fsc.xml | 10.2 KB | Display | FSC data file |
Images | emd_21410.png | 115.7 KB | ||
Filedesc metadata | emd-21410.cif.gz | 5.1 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21410 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21410 | HTTPS FTP |
-Related structure data
Related structure data | 6vw2MC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-10871 (Title: Cryo electron microscopy of recombinant, un-seeded hIAPP fibrils Data size: 1.9 TB Data #1: Unaligned K2 movies of unseeded, recombinant hIAPP amyloid fibrils [micrographs - multiframe]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21410.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 1.064 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : hIAPP fibril
Entire | Name: hIAPP fibril |
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Components |
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-Supramolecule #1: hIAPP fibril
Supramolecule | Name: hIAPP fibril / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Islet amyloid polypeptide (SUMO-tagged)
Macromolecule | Name: Islet amyloid polypeptide (SUMO-tagged) / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 17.274273 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MGSSHHHHHH GSGLVPRGSA SMSDSEVNQE AKPEVKPEVK PETHINLKVS DGSSEIFFKI KKTTPLRRLM EAFAKRQGKE MDSLRFLYD GIRIQADQTP EDLDMEDNDI IEAHREQIGK CNTATCATQR LANFLVHSSN NFGAILSSTN VGSNTY UniProtKB: Ubiquitin-like protein SMT3, Islet amyloid polypeptide |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | helical reconstruction |
Aggregation state | filament |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 2.0 µm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average exposure time: 8.0 sec. / Average electron dose: 44.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |