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- PDB-6zrq: two-protofilament amyloid structure of S20G variant of human amyl... -

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Basic information

Entry
Database: PDB / ID: 6zrq
Titletwo-protofilament amyloid structure of S20G variant of human amylin (IAPP - islet amyloid polypeptide)
ComponentsIslet amyloid polypeptide
KeywordsPROTEIN FIBRIL / amyloid fibril type-2-diabetes early-onset
Function / homology
Function and homology information


amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of protein kinase A signaling / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / bone resorption ...amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of protein kinase A signaling / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / bone resorption / sensory perception of pain / positive regulation of calcium-mediated signaling / osteoclast differentiation / hormone 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
Similarity search - Function
Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / 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
AuthorsGallardo, R.U. / Iadanza, M.G. / Ranson, N.A. / Radford, S.E.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Wellcome TrustWT 204963 United Kingdom
Wellcome Trust108466/Z/15/Z United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly.
Authors: Rodrigo Gallardo / Matthew G Iadanza / Yong Xu / George R Heath / Richard Foster / Sheena E Radford / Neil A Ranson /
Abstract: Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G ...Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. Here we report cryo-EM structures of amyloid fibrils of wild-type human amylin and its S20G variant. The wild-type fibril structure, solved to 3.6-Å resolution, contains two protofilaments, each built from S-shaped subunits. S20G fibrils, by contrast, contain two major polymorphs. Their structures, solved at 3.9-Å and 4.0-Å resolution, respectively, share a common two-protofilament core that is distinct from the wild-type structure. Remarkably, one polymorph contains a third subunit with another, distinct, cross-β conformation. The presence of two different backbone conformations within the same fibril may explain the increased aggregation propensity of S20G, and illustrates a potential structural basis for surface-templated fibril assembly.
History
DepositionJul 14, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Derived calculations
Category: pdbx_struct_sheet_hbond / struct_sheet ...pdbx_struct_sheet_hbond / struct_sheet / struct_sheet_order / struct_sheet_range
Revision 1.2Nov 18, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

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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
K: Islet amyloid polypeptide
L: Islet amyloid polypeptide


Theoretical massNumber of molelcules
Total (without water)46,54012
Polymers46,54012
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area21440 Å2
ΔGint-64 kcal/mol
Surface area9710 Å2
MethodPISA

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Components

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


Mass: 3878.293 Da / Num. of mol.: 12 / Mutation: S20G / Source method: obtained synthetically / Details: TYC = C-terminal amidated Tyr / Source: (synth.) Homo sapiens (human) / References: UniProt: P10997
Has ligand of interestN

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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

Component
IDNameTypeEntity IDParent-IDSource
1two-protofilament amyloid fibrils of S20G variant of amylinCOMPLEXall0MULTIPLE SOURCES
2two-protofilament amyloid fibrils of S20G variant of amylinCOMPLEXall1RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: synthetic construct (others)
Buffer solutionpH: 6.8
Buffer componentConc.: 20 mM / Name: ammonium acetate / Formula: NH4CH3CO
SpecimenConc.: 0.12 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Synthetically produced, oxidised and C-terminally amidated
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Homemade
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 85 % / Chamber temperature: 277 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 FIELD / Nominal magnification: 130000 X / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 13 sec. / Electron dose: 54.73 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 52

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Processing

EM software
IDNameVersionCategory
1RELION3particle selection
2EPU2.5.0.4799RELimage acquisition
4Gctf1.18CTF correction
11RELION3classification
12RELION33D reconstruction
13PHENIX1.17model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.05 ° / Axial rise/subunit: 2.41 Å / Axial symmetry: C1
Particle selectionNum. of particles selected: 64274
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 11901 / Num. of class averages: 1 / Symmetry type: HELICAL

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