|Entry||Database: PDB / ID: 7m62|
|Title||Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 2|
|Components||Islet amyloid polypeptideAmylin|
|Keywords||PROTEIN FIBRIL / hIAPP / type II diabetes / amyloid|
|Function / homology|
Function and homology information
positive regulation of calcium ion import across plasma membrane / amylin receptor signaling pathway / Calcitonin-like ligand receptors / eating behavior / negative regulation of mitochondrion organization / negative regulation of amyloid fibril formation / 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 / amylin receptor signaling pathway / Calcitonin-like ligand receptors / eating behavior / negative regulation of mitochondrion organization / negative regulation of amyloid fibril formation / 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 protein kinase B signaling / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / Amyloid fiber formation / positive regulation of apoptotic process / negative regulation of cell population proliferation / 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, conserved site / Calcitonin-like / calcitonin / Calcitonin peptide-like / Calcitonin / CGRP / IAPP family signature. / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family
Similarity search - Domain/homology
Islet amyloid polypeptide
Similarity search - Component
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.9 Å|
|Authors||Cao, Q. / Boyer, D.R. / Sawaya, M.R. / Eisenberg, D.S.|
|Funding support|| United States, 1items |
|Citation||Journal: 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.
|Structure viewer||Molecule: |
Downloads & links
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
|Symmetry||Helical 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 °)|
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
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction|
|Component||Name: 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 weight||Units: KILODALTONS/NANOMETER / Experimental value: NO|
|Source (natural)||Organism: Homo sapiens (human)|
|Buffer solution||pH: 7.4 / Details: PBS buffer|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid material: COPPER / Grid type: Quantifoil R1.2/1.3|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 45 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 3|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Helical symmerty||Angular rotation/subunit: 178.42 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C2|
|3D reconstruction||Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 23957 / Symmetry type: HELICAL|
|Atomic model building||B value: 98 / Protocol: AB INITIO MODEL / Space: REAL|
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