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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)
Verlagsversion Postprint Forschungsdaten DOI
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift eLife
Quellenangaben Band: 6, Heft: , Seiten: , Artikelnummer: e31226 Supplement: ,
Verlag eLife Sciences Publications
Verlagsort Cambridge
Begutachtungsstatus Peer reviewed