Atomic resolution structure of full- length human insulin fibrils

• 成果类型: Article
• 署名作者: Suladze, Saba; Sarkar, Riddhiman; Rodina, Natalia; Bokvist, Krister; Krewinkel, Manuel; Scheps, Daniel; Nagel, Norbert; Bardiaux, Benjamin; Reif, Bernd
• 署名单位: Technical University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Sanofi-Aventis; Sanofi Germany; Sanofi-Aventis; Sanofi Germany; Sanofi-Aventis; Sanofi Germany; Sanofi-Aventis; Sanofi Germany; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Pasteur Network; Universite Paris Cite; Institut Pasteur Paris; Centre National de la Recherche Scientifique (CNRS); CNRS - National Institute for Biology (INSB); Neurocrine Biosciences; AbbVie
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12354
• DOI: 10.1073/pnas.2401458121
• 发表日期: 2024-06-04
• 关键词: solid-state nmr; small-angle scattering; amyloid fibrils; protein structures; molecular-structure; injection sites; assignments; aggregation; STABILITY; backbone

摘要

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 (3- 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.