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- PDB-7m62: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -

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Basic information

Entry
Database: PDB / ID: 7m62
TitleCryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 2
ComponentsIslet amyloid polypeptideAmylin
KeywordsPROTEIN FIBRIL / hIAPP / type II diabetes / amyloid
Function / homology
Function and homology information


positive regulation of calcium ion import across plasma membrane / Calcitonin-like ligand receptors / amylin receptor signaling pathway / eating behavior / negative regulation of amyloid fibril formation / negative regulation of mitochondrion organization / negative regulation of bone resorption / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly ...positive regulation of calcium ion import across plasma membrane / Calcitonin-like ligand receptors / amylin receptor signaling pathway / eating behavior / negative regulation of amyloid fibril formation / negative regulation of mitochondrion organization / negative regulation of bone resorption / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / negative regulation of cell differentiation / inclusion body / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of cell death / sensory perception of pain / protein destabilization / G alpha (s) signalling events / protein homooligomerization / hormone activity / negative regulation of inflammatory response to antigenic stimulus / cell-cell signaling / amyloid-beta binding / positive regulation of cytosolic calcium ion concentration / positive regulation of MAPK cascade / positive regulation of peptidyl-serine phosphorylation / amyloid fibril formation / positive regulation of ERK1 and ERK2 cascade / positive regulation of protein kinase B signaling / G protein-coupled receptor signaling pathway / Amyloid fiber formation / negative regulation of cell population proliferation / positive regulation of apoptotic process / signaling receptor binding / neuronal cell body / apoptotic process / positive regulation of gene expression / signal transduction / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Islet amyloid polypeptide / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin, conserved site / Calcitonin peptide-like / Calcitonin-like / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family
Similarity search - Domain/homology
Islet amyloid polypeptide
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsCao, Q. / Boyer, D.R. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG0543022 United States
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores.
Authors: Qin Cao / David R Boyer / Michael R Sawaya / Romany Abskharon / Lorena Saelices / Binh A Nguyen / Jiahui Lu / Kevin A Murray / Fouad Kandeel / David S Eisenberg /
Abstract: Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world's population. To visualize disease-relevant ...Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world's population. To visualize disease-relevant hIAPP fibrils, we extracted amyloid fibrils from islet cells of a T2D donor and amplified their quantity by seeding synthetic hIAPP. Cryo-EM studies revealed four fibril polymorphic atomic structures. Their resemblance to four unseeded hIAPP fibrils varies from nearly identical (TW3) to non-existent (TW2). The diverse repertoire of hIAPP polymorphs appears to arise from three distinct protofilament cores entwined in different combinations. The structural distinctiveness of TW1, TW2 and TW4 suggests they may be faithful replications of the pathogenic seeds. If so, the structures determined here provide the most direct view yet of hIAPP amyloid fibrils formed during T2D.
History
DepositionMar 25, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 22, 2021Provider: repository / Type: Initial release

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Assembly

Deposited unit
A: Islet amyloid polypeptide
B: Islet amyloid polypeptide
C: Islet amyloid polypeptide
D: Islet amyloid polypeptide
E: Islet amyloid polypeptide
F: Islet amyloid polypeptide
G: Islet amyloid polypeptide
H: Islet amyloid polypeptide
I: Islet amyloid polypeptide
J: Islet amyloid polypeptide


Theoretical massNumber of molelcules
Total (without water)39,07310
Polymers39,07310
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
SymmetryHelical symmetry: (Circular symmetry: 2 / Dyad axis: no / N subunits divisor: 1 / Num. of operations: 10 / Rise per n subunits: 4.8 Å / Rotation per n subunits: 178.42 °)

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Components

#1: Protein/peptide
Islet amyloid polypeptide / Amylin / Amylin / Diabetes-associated peptide / DAP / Insulinoma amyloid peptide


Mass: 3907.312 Da / Num. of mol.: 10 / Fragment: C-terminal amidated peptide (UNP residues 34-70) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10997

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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: hIAPP fibril / Type: COMPLEX
Details: Synthetic hIAPP seeded by hIAPP fibrils extracted from a patient with Type II Diabetes
Entity ID: #1 / Source: NATURAL
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4 / Details: PBS buffer
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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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 FIELDBright-field microscopy
Image recordingElectron dose: 45 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 3

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Processing

EM software
IDNameVersionCategoryDetails
1EMAN2particle selectione2helixboxer.py
2SerialEMimage acquisition
4CTFFIND4.1.8CTF correction
9RELION2initial Euler assignment
10RELION2final Euler assignment
12RELION23D reconstruction
13PHENIXreal_space_refinemodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 178.42 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23957 / Symmetry type: HELICAL
Atomic model buildingB value: 98 / Protocol: AB INITIO MODEL / Space: REAL

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