TY - JOUR
T1 - Disulfide bridges remain intact while native insulin converts into amyloid fibrils
AU - Kurouski, Dmitry
AU - Washington, Jacqueline
AU - Ozbil, Mehmet
AU - Prabhakar, Rajeev
AU - Shekhtman, Alexander
AU - Lednev, Igor K.
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - Amyloid fibrils are β-sheet-rich protein aggregates commonly found in the organs and tissues of patients with various amyloid-associated diseases. Understanding the structural organization of amyloid fibrils can be beneficial for the search of drugs to successfully treat diseases associated with protein misfolding. The structure of insulin fibrils was characterized by deep ultraviolet resonance Raman (DUVRR) and Nuclear Magnetic Resonance (NMR) spectroscopy combined with hydrogen-deuterium exchange. The compositions of the fibril core and unordered parts were determined at single amino acid residue resolution. All three disulfide bonds of native insulin remained intact during the aggregation process, withstanding scrambling. Three out of four tyrosine residues were packed into the fibril core, and another aromatic amino acid, phenylalanine, was located in the unordered parts of insulin fibrils. In addition, using all-atom MD simulations, the disulfide bonds were confirmed to remain intact in the insulin dimer, which mimics the fibrillar form of insulin.
AB - Amyloid fibrils are β-sheet-rich protein aggregates commonly found in the organs and tissues of patients with various amyloid-associated diseases. Understanding the structural organization of amyloid fibrils can be beneficial for the search of drugs to successfully treat diseases associated with protein misfolding. The structure of insulin fibrils was characterized by deep ultraviolet resonance Raman (DUVRR) and Nuclear Magnetic Resonance (NMR) spectroscopy combined with hydrogen-deuterium exchange. The compositions of the fibril core and unordered parts were determined at single amino acid residue resolution. All three disulfide bonds of native insulin remained intact during the aggregation process, withstanding scrambling. Three out of four tyrosine residues were packed into the fibril core, and another aromatic amino acid, phenylalanine, was located in the unordered parts of insulin fibrils. In addition, using all-atom MD simulations, the disulfide bonds were confirmed to remain intact in the insulin dimer, which mimics the fibrillar form of insulin.
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U2 - 10.1371/journal.pone.0036989
DO - 10.1371/journal.pone.0036989
M3 - Article
C2 - 22675475
AN - SCOPUS:84861730624
VL - 7
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 6
M1 - e36989
ER -