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- EMDB-40305: Cryo-EM structure of insulin amyloid-like fibril that is composed... -
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Basic information
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Title | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments | |||||||||
![]() | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. | |||||||||
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![]() | amyloid-like fibril / SIGNALING PROTEIN | |||||||||
Function / homology | ![]() negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of respiratory burst / positive regulation of peptide hormone secretion / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of cellular amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / acute-phase response / Regulation of insulin secretion / endosome lumen / positive regulation of glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin-like growth factor receptor binding / insulin receptor binding / wound healing / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / regulation of protein localization / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Wang LW / Hall C / Uchikawa E / Chen DL / Choi E / Zhang XW / Bai XC | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis of insulin fibrillation. Authors: Liwei Wang / Catherine E Hall / Emiko Uchikawa / Dailu Chen / Eunhee Choi / Xuewu Zhang / Xiao-Chen Bai / ![]() Abstract: Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and ...Insulin is a hormone responsible for maintaining normal glucose levels by activating insulin receptor (IR) and is the primary treatment for diabetes. However, insulin is prone to unfolding and forming cross-β fibers. Fibrillation complicates insulin storage and therapeutic application. Molecular details of insulin fibrillation remain unclear, hindering efforts to prevent fibrillation process. Here, we characterized insulin fibrils using cryo-electron microscopy (cryo-EM), showing multiple forms that contain one or more of the protofilaments containing both the A and B chains of insulin linked by disulfide bonds. We solved the cryo-EM structure of one of the fibril forms composed of two protofilaments at 3.2-Å resolution, which reveals both the β sheet conformation of the protofilament and the packing interaction between them that underlie the fibrillation. On the basis of this structure, we designed several insulin mutants that display reduced fibrillation while maintaining native IR signaling activity. These designed insulin analogs may be developed into more effective therapeutics for type 1 diabetes. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 2.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.2 KB 17.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 7.4 KB | Display | ![]() |
Images | ![]() | 27.4 KB | ||
Others | ![]() ![]() | 25.6 MB 25.5 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8sbdMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Cryo-EM structure of insulin amyloid-like fibril that is...
File | emd_40305_half_map_1.map | ||||||||||||
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Annotation | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. Half map 1. | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Cryo-EM structure of insulin amyloid-like fibril that is...
File | emd_40305_half_map_2.map | ||||||||||||
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Annotation | Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments. Half map 2. | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Cryo-EM structure of insulin amyloid-like fibril that is composed...
Entire | Name: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments |
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Components |
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-Supramolecule #1: Cryo-EM structure of insulin amyloid-like fibril that is composed...
Supramolecule | Name: Cryo-EM structure of insulin amyloid-like fibril that is composed of two antiparallel protofilaments type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Insulin B chain
Macromolecule | Name: Insulin B chain / type: protein_or_peptide / ID: 1 / Number of copies: 16 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 3.433953 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: FVNQHLCGSH LVEALYLVCG ERGFFYTPKT UniProtKB: Insulin |
-Macromolecule #2: Insulin A chain
Macromolecule | Name: Insulin A chain / type: protein_or_peptide / ID: 2 / Number of copies: 16 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 2.383698 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GIVEQCCTSI CSLYQLENYC N UniProtKB: Insulin |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | filament |
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Sample preparation
Concentration | 1 mg/mL |
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Buffer | pH: 2 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Average exposure time: 8.0 sec. / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-8sbd: |