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Rodriguez Camargo, D.C.* ; Korshavn, K.J.* ; Jussupow, A.* ; Raltchev, K.* ; Goricanec, D.* ; Fleisch, M. ; Sarkar, R.* ; Xue, K. ; Aichler, M. ; Mettenleiter, G. ; Walch, A.K. ; Camilloni, C.* ; Hagn, F. ; Reif, B. ; Ramamoorthy, A.*

Stabilization and structural analysis of a membrane-associated hIAPP aggregation intermediate.

eLife 6:e31226 (2017)
Publ. Version/Full Text Postprint Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Membrane-assisted amyloid formation is implicated in human diseases, and many of the aggregating species accelerate amyloid formation and induce cell death. While structures of membrane-associated intermediates would provide tremendous insights into the pathology and aid in the design of compounds to potentially treat the diseases, it has not been feasible to overcome the challenges posed by the cell membrane. Here we use NMR experimental constraints to solve the structure of a type-2 diabetes related human islet amyloid polypeptide intermediate stabilized in nanodiscs. ROSETTA and MD simulations resulted in a unique b-strand structure distinct from the conventional amyloid b-hairpin and revealed that the nucleating NFGAIL region remains flexible and accessible within this isolated intermediate, suggesting a mechanism by which membrane-associated aggregation may be propagated. The ability of nanodiscs to trap amyloid intermediates as demonstrated could become one of the most powerful approaches to dissect the complicated misfolding pathways of protein aggregation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Biochemistry ; Biophysics ; Structural Biology; Islet Amyloid Polypeptide; Alpha-synuclein; Biological-membranes; Structure Generation; Protein Aggregation; Bilayer Nanodiscs; Nmr-spectroscopy; Force-field; Beta; Peptide
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Journal eLife
Quellenangaben Volume: 6, Issue: , Pages: , Article Number: e31226 Supplement: ,
Publisher eLife Sciences Publications
Publishing Place Cambridge
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Research Unit Analytical Pathology (AAP)