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Mutual structural effects of unmodified and pyroglutamylated amyloid β peptides during aggregation
Author(s) -
Abedin Faisal,
Tatulian Suren A.
Publication year - 2021
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.3312
Subject(s) - chemistry , fibrillogenesis , circular dichroism , thioflavin , protein secondary structure , beta sheet , fourier transform infrared spectroscopy , fibril , peptide , amyloid (mycology) , protein structure , biophysics , crystallography , biochemistry , alzheimer's disease , biology , medicine , inorganic chemistry , physics , disease , pathology , quantum mechanics
Amyloid β (Aβ) peptide aggregates are linked to Alzheimer's disease (AD). Posttranslationally pyroglutamylated Aβ (pEAβ) occurs in AD brains in significant quantities and is hypertoxic, but the underlying structural and aggregation properties remain poorly understood. Here, the structure and aggregation of Aβ 1–40 and pEAβ 3–40 are analyzed separately and in equimolar combination. Circular dichroism data show that Aβ 1–40 , pEAβ 3–40 , and their combination assume α‐helical structure in dry state and transition to unordered structure in aqueous buffer. Aβ 1–40 and the 1:1 combination gradually acquire β‐sheet structure while pEAβ 3–40 adopts an α‐helix/β‐sheet conformation. Thioflavin‐T fluorescence studies suggest that the two peptides mutually inhibit fibrillogenesis. Fourier transform infrared (FTIR) spectroscopy identifies the presence of β‐turn and α‐helical structures in addition to β‐sheet structure in peptides in aqueous buffer. The kinetics of transitions from the initial α‐helical structure to β‐sheet structure were resolved by slow hydration of dry peptides by D 2 O vapor, coupled with isotope‐edited FTIR. These data confirmed the mutual suppression of β‐sheet formation by the two peptides. Remarkably, pEAβ 3–40 maintained a significant fraction of α‐helical structure in the combined sample, implying a reduced β‐sheet propensity of pEAβ 3–40 . Altogether, the data imply that the combination of unmodified and pyroglutamylated Aβ peptides resists fibrillogenesis and favors the prefibrillar state, which may underlie hypertoxicity of pEAβ.