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- EMDB-8272: Human Islet Amyloid Polypeptide Segment 19-SGNNFGAILSS-29 with Ea... -

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Basic information

Entry
Database: EMDB / ID: EMD-8272
TitleHuman Islet Amyloid Polypeptide Segment 19-SGNNFGAILSS-29 with Early Onset S20G Mutation Determined by MicroED
Map dataSigma-A-weighted 2Fo-Fc map
Sample
  • Complex: Amyloid fiber
    • Protein or peptide: hIAPP(residues 19-29)S20G
  • Ligand: water
KeywordsAmyloid / islet amyloid polypeptide / Type II Diabetes / Toxic Spine / MicroED / PROTEIN FIBRIL
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 / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly ...: / amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / negative regulation of osteoclast differentiation / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / 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 / 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 crystallography / cryo EM / Resolution: 1.9 Å
AuthorsKrotee PAL / Rodriguez JA
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01 AG029430 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Elife / Year: 2017
Title: Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.
Authors: Pascal Krotee / Jose A Rodriguez / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Johan Hattne / Brent L Nannenga / Marie E Oskarsson / Stephan Philipp / Sarah Griner / Lin ...Authors: Pascal Krotee / Jose A Rodriguez / Michael R Sawaya / Duilio Cascio / Francis E Reyes / Dan Shi / Johan Hattne / Brent L Nannenga / Marie E Oskarsson / Stephan Philipp / Sarah Griner / Lin Jiang / Charles G Glabe / Gunilla T Westermark / Tamir Gonen / David S Eisenberg /
Abstract: hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β- ...hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP.
History
DepositionJun 28, 2016-
Header (metadata) releaseOct 5, 2016-
Map releaseDec 21, 2016-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.16
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.16
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8272.png

Downloads & links

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Map

FileDownload / File: emd_8272.map.gz / Format: CCP4 / Size: 291 KB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSigma-A-weighted 2Fo-Fc map
Voxel sizeX: 0.3983 Å / Y: 0.5813 Å / Z: 0.6321 Å
Density
Contour LevelBy EMDB: 0.14 / Movie #1: 0.16
Minimum - Maximum-0.46300763 - 0.8558442
Average (Standard dev.)0.009700047 (±0.17939538)
SymmetrySpace group: 19
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin-7-29-45
Dimensions194391
Spacing1232112
CellA: 4.7796 Å / B: 18.6016 Å / C: 70.7952 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.398333333333330.58131250.63209821428571
M x/y/z1232112
origin x/y/z0.0000.0000.000
length x/y/z4.78018.60270.795
α/β/γ90.00090.00090.000
start NX/NY/NZ-7-29-45
NX/NY/NZ194391
MAP C/R/S213
start NC/NR/NS-29-7-45
NC/NR/NS431991
D min/max/mean-0.4630.8560.010

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Supplemental data

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Sample components

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Entire : Amyloid fiber

EntireName: Amyloid fiber
Components
  • Complex: Amyloid fiber
    • Protein or peptide: hIAPP(residues 19-29)S20G
  • Ligand: water

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Supramolecule #1: Amyloid fiber

SupramoleculeName: Amyloid fiber / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Molecular weightTheoretical: 4.441 kDa/nm

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Macromolecule #1: hIAPP(residues 19-29)S20G

MacromoleculeName: hIAPP(residues 19-29)S20G / type: protein_or_peptide / ID: 1 / Details: islet amyloid / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.066125 KDa
SequenceString:
SGNNFGAILS S

UniProtKB: Islet amyloid polypeptide

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Macromolecule #2: water

MacromoleculeName: water / type: ligand / ID: 2 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron crystallography
Aggregation state3D array

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Sample preparation

Concentration1.066 mg/mL
BufferpH: 7.4
Component:
NameConcentration
phosphate-buffered saline
DMSODimethyl sulfoxide1.0 %
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Support film - Film thickness: 30 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE
Crystal formationInstrument: 1.5 mL Eppendorf tube / Atmosphere: Air, sealed chamber. / Temperature: 298.0 K / Time: 2.0 DAY
Details: 1 mM lyophilized peptide in PBS with 1% DMSO at room temperature under quiescent conditions. Crystals grew in a few hours and reached full size within 15 hours.

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Electron microscopy

MicroscopeFEI TECNAI 20
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Camera length: 1840 mm
Sample stageSpecimen holder model: GATAN 626 SINGLE TILT LIQUID NITROGEN CRYO TRANSFER HOLDER
Cooling holder cryogen: NITROGEN
TemperatureMin: 100.0 K / Max: 100.0 K
Image recordingFilm or detector model: TVIPS TEMCAM-F416 (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 2 / Number diffraction images: 879 / Average exposure time: 2.0 sec. / Average electron dose: 0.01 e/Å2
Details: The detector was operated in rolling shutter mode with 2x2 pixel binning.

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Image processing

Crystallography statisticsNumber intensities measured: 1380 / Number structure factors: 548 / Fourier space coverage: 83 / R sym: 0.106 / R merge: 0.106 / Overall phase error: 0.01 / Overall phase residual: 0.01 / Phase error rejection criteria: 0 / High resolution: 1.9 Å
Details: Phasing statistics are not applicable. No imaging was used. The phases were obtained using molecular replacement.
Shell:
Shell IDHigh resolutionLow resolutionNumber structure factorsPhase residualFourier space coverageMultiplicity
14.25 Å22.0 Å590.0181.9000000000000062.63
23.01 Å4.24 Å1100.0190.9000000000000062.78
32.45 Å3.0 Å1110.0193.2999999999999972.85
42.13 Å2.44 Å1530.0189.52.5
51.9 Å2.12 Å1150.0164.5999999999999941.92
Molecular replacementSoftware - Name: Phaser (ver. 2.5.6)
Startup modelType of model: INSILICO MODEL / Details: idealized 7-residue polyalanine beta-strand
Final reconstructionResolution.type: BY AUTHOR / Resolution: 1.9 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES

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Atomic model buiding 1

RefinementSpace: RECIPROCAL / Protocol: OTHER / Overall B value: 14.512 / Target criteria: maximum likelihood
Output model

PDB-5knz:
Human Islet Amyloid Polypeptide Segment 19-SGNNFGAILSS-29 with Early Onset S20G Mutation Determined by MicroED

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