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Suladze, S. ; Sarkar, R. ; Rodina, N.* ; Bokvist, K.* ; Krewinkel, M.* ; Scheps, D.* ; Nagel, N.* ; Bardiaux, B.* ; Reif, B.

Atomic resolution structure of full-length human insulin fibrils.

Proc. Natl. Acad. Sci. U.S.A. 121:e2401458121 (2024)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Patients with type 1 diabetes mellitus who are dependent on an external supply of insulin develop insulin-derived amyloidosis at the sites of insulin injection. A major component of these plaques is identified as full-length insulin consisting of the two chains A and B. While there have been several reports that characterize insulin misfolding and the biophysical properties of the fibrils, atomic-level information on the insulin fibril architecture remains elusive. We present here an atomic resolution structure of a monomorphic insulin amyloid fibril that has been determined using magic angle spinning solid-state NMR spectroscopy. The structure of the insulin monomer yields a U-shaped fold in which the two chains A and B are arranged in parallel to each other and are oriented perpendicular to the fibril axis. Each chain contains two β-strands. We identify two hydrophobic clusters that together with the three preserved disulfide bridges define the amyloid core structure. The surface of the monomeric amyloid unit cell is hydrophobic implicating a potential dimerization and oligomerization interface for the assembly of several protofilaments in the mature fibril. The structure provides a starting point for the development of drugs that bind to the fibril surface and disrupt secondary nucleation as well as for other therapeutic approaches to attenuate insulin aggregation.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mas Solid-state Nmr ; Saxs ; Amyloid Fibril Structure ; Molecular Modeling; Solid-state Nmr; Small-angle Scattering; Amyloid Fibrils; Protein Structures; Molecular-structure; Injection Sites; Assignments; Aggregation; Stability; Backbone
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 121, Heft: 23, Seiten: , Artikelnummer: e2401458121 Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503090-001
Förderungen Helmholtz-Gemeinschaft
German Research Foundation (Deutsche Forschungsgemeinschaft, DFG)
DOI 10.1073/pnas.2401458121
WOS ID 001241393200003
Scopus ID 85194836269
PubMed ID 38809711
Erfassungsdatum 2024-06-17
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