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- EMDB-21410: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -

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Basic information

Entry
Database: EMDB / ID: EMD-21410
TitleCryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils
Map data
Sample
  • Organelle or cellular component: hIAPP fibril
    • Protein or peptide: Islet amyloid polypeptide (SUMO-tagged)
KeywordshIAPP / 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) / SUMO is proteolytically processed / SUMOylation of transcription factors / SUMOylation of transcription cofactors / Postmitotic nuclear pore complex (NPC) reformation / septin ring / SUMOylation of DNA damage response and repair proteins / amylin receptor 3 signaling pathway ...SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / SUMOylation of transcription factors / SUMOylation of transcription cofactors / Postmitotic nuclear pore complex (NPC) reformation / septin ring / SUMOylation of DNA damage response and repair proteins / amylin receptor 3 signaling pathway / amylin receptor 2 signaling pathway / Transcriptional and post-translational regulation of MITF-M expression and activity / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / SUMOylation of DNA replication proteins / Calcitonin-like ligand receptors / SUMOylation of SUMOylation proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / negative regulation of amyloid fibril formation / SUMOylation of RNA binding proteins / SUMOylation of chromatin organization proteins / negative regulation of bone resorption / eating behavior / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / positive regulation of cAMP/PKA signal transduction / ubiquitin-like protein ligase binding / protein sumoylation / bone resorption / negative regulation of protein-containing complex assembly / sensory perception of pain / positive regulation of calcium-mediated signaling / 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 / positive regulation of apoptotic process / receptor ligand activity / Amyloid fiber formation / signaling receptor binding / neuronal cell body / apoptotic process / lipid binding / signal transduction / extracellular space / extracellular region / identical protein binding / nucleus
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 / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like ...Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Islet amyloid polypeptide / Ubiquitin-like protein SMT3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsCao Q / Boyer DR
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG0543022 United States
CitationJournal: 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
DepositionFeb 18, 2020-
Header (metadata) releaseJun 10, 2020-
Map releaseJun 10, 2020-
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: 2
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6vw2
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6vw2
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21410.png

Downloads & links

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Map

FileDownload / File: emd_21410.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 128 pix.
= 136.192 Å		1.06 Å/pix.
x 128 pix.
= 136.192 Å		1.06 Å/pix.
x 128 pix.
= 136.192 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0 / Movie #1: 2
Minimum - Maximum-8.656466 - 14.139030999999999
Average (Standard dev.)-0.000000000003456 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-64-64-64
Dimensions128128128
Spacing128128128
CellA=B=C: 136.192 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0641.0641.064
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z136.192136.192136.192
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S321
start NC/NR/NS-64-64-64
NC/NR/NS128128128
D min/max/mean-8.65614.139-0.000

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Supplemental data

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Sample components

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Entire : hIAPP fibril

EntireName: hIAPP fibril
Components
  • Organelle or cellular component: hIAPP fibril
    • Protein or peptide: Islet amyloid polypeptide (SUMO-tagged)

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Supramolecule #1: hIAPP fibril

SupramoleculeName: hIAPP fibril / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Islet amyloid polypeptide (SUMO-tagged)

MacromoleculeName: Islet amyloid polypeptide (SUMO-tagged) / type: protein_or_peptide / ID: 1 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.274273 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGSSHHHHHH GSGLVPRGSA SMSDSEVNQE AKPEVKPEVK PETHINLKVS DGSSEIFFKI KKTTPLRRLM EAFAKRQGKE MDSLRFLYD GIRIQADQTP EDLDMEDNDI IEAHREQIGK CNTATCATQR LANFLVHSSN NFGAILSSTN VGSNTY

UniProtKB: Ubiquitin-like protein SMT3, Islet amyloid polypeptide

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm 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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 2.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.406 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.42 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2) / Number images used: 25767
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2)
FSC plot (resolution estimation)

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