1SF1

NMR STRUCTURE OF HUMAN INSULIN under Amyloidogenic Condition, 15 STRUCTURES

1SF1 の概要

• エントリーDOI: 10.2210/pdb1sf1/pdb
• 関連するPDBエントリー: 2HIU
• 分子名称: INSULIN A CHAIN, Insulin (2 entities in total)
• 機能のキーワード: hormone, human insulin, hormone-growth factor complex, hormone/growth factor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P01308 P01308
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 5817.65

構造登録者

Weiss, M.A.,Hua, Q.X. (登録日: 2004-02-19, 公開日: 2004-03-30, 最終更新日: 2024-11-06)

主引用文献

Hua, Q.X.,Weiss, M.A.
Mechanism of insulin fibrillation: the structure of insulin under amyloidogenic conditions resembles a protein-folding intermediate
J.Biol.Chem., 279:21449-21460, 2004

PubMed Abstract: Insulin undergoes aggregation-coupled misfolding to form a cross-beta assembly. Such fibrillation has long complicated its manufacture and use in the therapy of diabetes mellitus. Of interest as a model for disease-associated amyloids, insulin fibrillation is proposed to occur via partial unfolding of a monomeric intermediate. Here, we describe the solution structure of human insulin under amyloidogenic conditions (pH 2.4 and 60 degrees C). Use of an enhanced sensitivity cryogenic probe at high magnetic field avoids onset of fibrillation during spectral acquisition. A novel partial fold is observed in which the N-terminal segments of the A- and B-chains detach from the core. Unfolding of the N-terminal alpha-helix of the A-chain exposes a hydrophobic surface formed by native-like packing of the remaining alpha-helices. The C-terminal segment of the B-chain, although not well ordered, remains tethered to this partial helical core. We propose that detachment of N-terminal segments makes possible aberrant protein-protein interactions in an amyloidogenic nucleus. Non-cooperative unfolding of the N-terminal A-chain alpha-helix resembles that observed in models of proinsulin folding intermediates and foreshadows the extensive alpha --> beta transition characteristic of mature fibrils.

PubMed: 14988398
DOI: 10.1074/jbc.M314141200

実験手法

SOLUTION NMR