Cryo-EM Structure of the Full-length hnRNPA1 Amyloid Fibril |
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Affiliation: | 1. Institute of Protein Biochemistry, Ulm University, 89081 Ulm, Germany;2. Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany;3. Core Unit Mass Spectrometry and Proteomics, Ulm University, 89081 Ulm, Germany;4. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA;5. Institute of Physics, University of Augsburg, 86159 Augsburg, Germany;6. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;1. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), c/ Nicolás Cabrera 1, Campus de Cantoblanco-UAM, Madrid, Spain;2. Department of Theoretical Condensed Matter Physics, Universidad Autónoma de Madrid, Spain;3. Department of Biotechnology, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain;1. Department of Microbiology and Immunology, Center for Infectious Disease Research, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA;2. Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA;1. Chair of Biopolymer Chemistry, Technical University of Munich, Freising, Germany;2. Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany;3. Institute of Organic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany |
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Abstract: | Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-21 screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding. |
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Keywords: | amyloid fibril structure amyloidosis Cryo-electron microscopy heterogeneous nuclear ribonuclear A1 protein misfolding hnRNPA1" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" Heterogeneous nuclear ribonucleoprotein A1 ALS" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" Amyotrophic lateral sclerosis FTLD" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" Frontotemporal lobar degeneration MSP" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" Multisystem proteinopathy RRM" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" RNA recognition motif LCD" },{" #name" :" keyword" ," $" :{" id" :" k0085" }," $$" :[{" #name" :" text" ," _" :" Low-complexity domain NLS" },{" #name" :" keyword" ," $" :{" id" :" k0095" }," $$" :[{" #name" :" text" ," _" :" Nuclear-localization signal sequence Kapβ2" },{" #name" :" keyword" ," $" :{" id" :" k0105" }," $$" :[{" #name" :" text" ," _" :" Karyopherin-β2 SG" },{" #name" :" keyword" ," $" :{" id" :" k0115" }," $$" :[{" #name" :" text" ," _" :" Stress granule WT" },{" #name" :" keyword" ," $" :{" id" :" k0125" }," $$" :[{" #name" :" text" ," _" :" Wildtype cryo-EM" },{" #name" :" keyword" ," $" :{" id" :" k0135" }," $$" :[{" #name" :" text" ," _" :" cryo-Electron microscopy 2D" },{" #name" :" keyword" ," $" :{" id" :" k0145" }," $$" :[{" #name" :" text" ," _" :" Two-dimensional 3D" },{" #name" :" keyword" ," $" :{" id" :" k0155" }," $$" :[{" #name" :" text" ," _" :" Three-dimensional FSC" },{" #name" :" keyword" ," $" :{" id" :" k0165" }," $$" :[{" #name" :" text" ," _" :" Fourier shell correlation TEM" },{" #name" :" keyword" ," $" :{" id" :" k0175" }," $$" :[{" #name" :" text" ," _" :" Transmission electron microscope MD" },{" #name" :" keyword" ," $" :{" id" :" k0185" }," $$" :[{" #name" :" text" ," _" :" Molecular dynamics RMSF" },{" #name" :" keyword" ," $" :{" id" :" k0195" }," $$" :[{" #name" :" text" ," _" :" Root mean square fluctuation RMSD" },{" #name" :" keyword" ," $" :{" id" :" k0205" }," $$" :[{" #name" :" text" ," _" :" Root mean square deviation HEPES" },{" #name" :" keyword" ," $" :{" id" :" k0215" }," $$" :[{" #name" :" text" ," _" :" 40 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid GST" },{" #name" :" keyword" ," $" :{" id" :" k0225" }," $$" :[{" #name" :" text" ," _" :" Glutathione S-transferase TEV" },{" #name" :" keyword" ," $" :{" id" :" k0235" }," $$" :[{" #name" :" text" ," _" :" Tobacco etch virus AB" },{" #name" :" keyword" ," $" :{" id" :" k0245" }," $$" :[{" #name" :" text" ," _" :" Assembly buffer EMDB" },{" #name" :" keyword" ," $" :{" id" :" k0255" }," $$" :[{" #name" :" text" ," _" :" Electron microscopy data bank PDB" },{" #name" :" keyword" ," $" :{" id" :" k0265" }," $$" :[{" #name" :" text" ," _" :" Protein data bank T" },{" #name" :" keyword" ," $" :{" id" :" k0275" }," $$" :[{" #name" :" text" ," _" :" Temperature N" },{" #name" :" keyword" ," $" :{" id" :" k0285" }," $$" :[{" #name" :" text" ," _" :" Particle number V" },{" #name" :" keyword" ," $" :{" id" :" k0295" }," $$" :[{" #name" :" text" ," _" :" Volume P" },{" #name" :" keyword" ," $" :{" id" :" k0305" }," $$" :[{" #name" :" text" ," _" :" Pressure EMBL" },{" #name" :" keyword" ," $" :{" id" :" k0315" }," $$" :[{" #name" :" text" ," _" :" European molecular biology laboratory PK" },{" #name" :" keyword" ," $" :{" id" :" k0325" }," $$" :[{" #name" :" text" ," _" :" Proteinase K |
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