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- PDB-6vw2: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -

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Basic information

Entry
Database: PDB / ID: 6vw2
TitleCryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils
ComponentsIslet amyloid polypeptide (SUMO-tagged)
KeywordsPROTEIN FIBRIL / hIAPP / type II diabetes / amyloid
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 speciesSaccharomyces cerevisiae (brewer's yeast)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.4 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: 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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 22, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: Islet amyloid polypeptide (SUMO-tagged)
B: Islet amyloid polypeptide (SUMO-tagged)
C: Islet amyloid polypeptide (SUMO-tagged)
D: Islet amyloid polypeptide (SUMO-tagged)
E: Islet amyloid polypeptide (SUMO-tagged)
F: Islet amyloid polypeptide (SUMO-tagged)
G: Islet amyloid polypeptide (SUMO-tagged)
H: Islet amyloid polypeptide (SUMO-tagged)
I: Islet amyloid polypeptide (SUMO-tagged)
J: Islet amyloid polypeptide (SUMO-tagged)


Theoretical massNumber of molelcules
Total (without water)172,74310
Polymers172,74310
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Islet amyloid polypeptide (SUMO-tagged) / Amylin / Diabetes-associated peptide / DAP / Insulinoma amyloid peptide


Mass: 17274.273 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (yeast), (gene. exp.) Homo sapiens (human)
Strain: ATCC 204508 / S288c / Gene: SMT3, YDR510W, D9719.15, IAPP / Production host: Escherichia coli (E. coli) / References: UniProt: Q12306, 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: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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 defocus max: 2000 nm / Nominal defocus min: 2000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Image recordingAverage exposure time: 8 sec. / Electron dose: 44 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategoryDetails
1EMAN2particle selectione2helixboxer.py
2Leginon3image acquisition
4CTFFIND4.1.8CTF correction
9PHENIXreal_space_refinemodel refinement
10RELION2initial Euler assignment
11RELION2final Euler assignment
13RELION23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: 179.42 ° / Axial rise/subunit: 2.406 Å / Axial symmetry: C1
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 25767 / Symmetry type: HELICAL

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