Amino acid substitutions [K16A] and [K28A] distinctly affect amyloid β-protein oligomerization

Abstract

Amyloid β-protein (Aβ) assembles into oligomers that play a seminal role in Alzheimer's disease (AD), a leading cause of dementia among the elderly. Despite undisputed importance of Aβ oligomers, their structure and the basis of their toxicity remain elusive. Previous experimental studies revealed that the [K16A] substitution strongly inhibits toxicity of the two predominant Aβ alloforms in the brain, Aβ 40 [K16A] substitution induces formation of more compact oligomers than the [K28A] substitution. If the structure-function paradigm applies to Aβ oligomers, then the observed substitution-specific structural changes in Aβ 40 and Aβ 42 oligomers are critical for understanding the structural basis of Aβ oligomer toxicity and correct identification of therapeutic targets against AD.

Flexible N‐Termini of Amyloid β‐Protein Oligomers: A Link between Structure and Activity?

“…revealed that changes to oligomer structure are both substitution‐ and alloform‐specific . The [K16A] substitution decreased β‐strand content more and produced more compact oligomer conformations in both Aβ 1–40 and Aβ 1–42 than the [K28A] substitution, implying that compaction of Aβ oligomers associated with reduced N‐terminal flexibility may underlie Aβ oligomer toxicity inhibition . These findings are consistent with in vitro findings by Kaden et al .…”

“…In line with this experimental study, DMD4B‐HYDRA simulations of [K16A]Aβ 1–40 , [K16A]Aβ 1–42 , [K28A]Aβ 1–40 , and [K28A]Aβ 1–42 oligomerization by Žganec et al . revealed that changes to oligomer structure are both substitution‐ and alloform‐specific . The [K16A] substitution decreased β‐strand content more and produced more compact oligomer conformations in both Aβ 1–40 and Aβ 1–42 than the [K28A] substitution, implying that compaction of Aβ oligomers associated with reduced N‐terminal flexibility may underlie Aβ oligomer toxicity inhibition .…”

“…[124] In line with this experimental study, DMD4B-HYDRA simulations of [K16A] Ab 1-40 , [K16A]Ab 1-42 , [K28A]Ab 1-40 , and [K28A]Ab 1-42 oligomerization by Ž ganec et al revealed that changes to oligomer structure are both substitution-and alloform-specific. [125] The [K16A] substitution decreased b-strand content more and produced more compact oligomer conformations in both Ab 1-40 and Ab 1-42 than the [K28A] substitution, implying that compaction of Ab oligomers associated with reduced Nterminal flexibility may underlie Ab oligomer toxicity inhibition [125]. These findings are consistent with in vitro findings by Kaden et al on FAD associated Ab mutants, [K16N]Ab 1-40 and [K16N]Ab , which exert reduced toxicities to cell cultures in comparison to WT peptides.…”

Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications

“…The role of familial mutations of α-synuclein charged residues was attributed to changes in fibril stability arising from alterations in electrostatic interactions [ 144 ]. A high impact of salt bridges was also shown for Aβ peptides, fibrils, and oligomer formation through β-turn stabilization [ 145 , 146 , 147 ]; the destabilization of intra-molecular salt bridges was suggested as a key factor in the copper ions’ binding effect on amyloid β fibrillization [ 148 , 149 ].…”

“…To conclude, MD simulations can provide a detailed model of the interaction, aggregation, and sometimes folding of the unfolded proteins, which can then be experimentally verified. It is useful, for example, in comparative investigation of point mutations effect, which is important in the case of amyloidogenic peptides associated with neurodegenerative diseases [ 144 , 147 ]. Notably, modeling of the unfolded protein (or flexible peptide) interactions requires multiple simulations, replica-exchange MD simulations, umbrella sampling, Markov state models, or other techniques to obtain reliable information about the conformational ensemble [ 133 ].…”