Inhibition of Aggregation of Amyloid β42 by Arginine-Containing Small Compounds

Kawasaki, Takayasu; Kamijo, Shunsuke

doi:10.1271/bbb.110879

Cited by 25 publications

(24 citation statements)

References 18 publications

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“…L-arginine is one of the most widely used agents effective in suppressing protein aggregation, assisting refolding of aggregated proteins, enhancing the solubility of aggregation-prone unfolded molecules, and stabilization of proteins during storage (see, for example, [ 147 ]). Dynamic light scattering measurements revealed that Arg (10–100 mM) dramatically accelerates the dithiothreitol-induced aggregation of acidic model proteins, including α-LA [ 148 ].…”

Section: Fibrillation Of α-Lactalbumin; Nanoparticles and Nanotubementioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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α-Lactalbumin (α-LA) is a small (Mr 14,200), acidic (pI 4–5), Ca2+-binding protein. α-LA is a regulatory component of lactose synthase enzyme system functioning in the lactating mammary gland. The protein possesses a single strong Ca2+-binding site, which can also bind Mg2+, Mn2+, Na+, K+, and some other metal cations. It contains several distinct Zn2+-binding sites. Physical properties of α-LA strongly depend on the occupation of its metal binding sites by metal ions. In the absence of bound metal ions, α-LA is in the molten globule-like state. The binding of metal ions, and especially of Ca2+, increases stability of α-LA against the action of heat, various denaturing agents and proteases, while the binding of Zn2+ to the Ca2+-loaded protein decreases its stability and causes its aggregation. At pH 2, the protein is in the classical molten globule state. α-LA can associate with membranes at neutral or slightly acidic pH at physiological temperatures. Depending on external conditions, α-LA can form amyloid fibrils, amorphous aggregates, nanoparticles, and nanotubes. Some of these aggregated states of α-LA can be used in practical applications such as drug delivery to tissues and organs. α-LA and some of its fragments possess bactericidal and antiviral activities. Complexes of partially unfolded α-LA with oleic acid are cytotoxic to various tumor and bacterial cells. α-LA in the cytotoxic complexes plays a role of a delivery carrier of cytotoxic fatty acid molecules into tumor and bacterial cells across the cell membrane. Perhaps in the future the complexes of α-LA with oleic acid will be used for development of new anti-cancer drugs.

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Section: Fibrillation Of α-Lactalbumin; Nanoparticles and Nanotubementioning

confidence: 99%

α-Lactalbumin, Amazing Calcium-Binding Protein

Permyakov

2020

Biomolecules

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“…According to recent studies investigating short peptides (which have a tendency to form amyloid fibrils), the aggregation reaction is purportedly caused by ionic amino acid residues such as lysine and glutamic acid, while hydrophobic interactions between aromatic amino acids have been proposed to be the promotion factors for fibril formation via π–π interactions [20, 26]. The ionic interactions between acidic and basic (i.e., arginine) residues have also been proposed to play an important role in the formation of toxic soluble oligomers of Aβ42 [10, 33]. An inhibition experiment using β-sheet breaker peptides indicates that the aggregation process of amyloid is reversible [23]; therefore, it is hypothesized that the fibrils are spontaneously refolded into their native form by dissociation of the aforementioned non-covalent bonds of the β-sheet clusters, or incorporation of water molecules into the hydrophobic core of the fibrils [25].…”

Section: Introductionmentioning

confidence: 99%

Effect of Mid-infrared Free-Electron Laser Irradiation on Refolding of Amyloid-Like Fibrils of Lysozyme into Native Form

et al. 2012

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Aggregation of lysozyme in an acidic solution generates inactive amyloid-like fibrils, with a broad infrared peak appearing at 1,610–1,630 cm−1, characteristic of a β-sheet rich structure. We report here that spontaneous refolding of these fibrils in water could be promoted by mid-infrared free-electron laser (mid-IR FEL) irradiation targeting the amide bands. The Fourier transform infrared spectrum of the fibrils reflected a β-sheet content that was as low as that of the native structure, following FEL irradiation at 1,620 cm−1 (amide I band); both transmission-electron microscopy imaging and Congo Red assay results also demonstrated a reduced fibril structure, and the enzymatic activity of lysozyme fibrils recovered to 70–90 % of the native form. Both irradiations at 1,535 cm−1(amide II band) and 1,240 cm−1 (amide III band) were also more effective for the refolding of the fibrils than mere heating in the absence of FEL. On the contrary, either irradiation at 1,100 or 2,000 cm−1 afforded only about 60 % recovery of lysozyme activity. These results indicate that the specific FEL irradiation tuned to amide bands is efficient in refolding of lysozyme fibrils into native form.

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“…To better understand how arginine mutations in the CDRs influence antibody affinity/specificity trade-offs, we have performed selections of single-chain antibody fragments (scFvs) against A␤42 in different solution environments that possess unique abilities to block non-specific interactions. Based on our previous findings for related A␤ V H domains (25,26) and the strong preference for A␤ to interact with arginine-rich peptides and proteins (27)(28)(29)(30)(31), we reasoned that the isolated antibodies would be enriched in arginine mutations in the CDRs using both weak and stringent selections for specificity. However, we posited that the unique specificities of the selected antibodies would provide important details about how arginine mutations in the CDRs impact antibody specificity.…”

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Arginine mutations in antibody complementarity-determining regions display context-dependent affinity/specificity trade-offs

Tiller

Kumar

et al. 2017

Journal of Biological Chemistry

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Antibodies commonly accumulate charged mutations in their complementarity-determining regions (CDRs) during affinity maturation to enhance electrostatic interactions. However, charged mutations can mediate non-specific interactions, and it is unclear to what extent CDRs can accumulate charged residues to increase antibody affinity without compromising specificity. This is especially concerning for positively charged CDR mutations that are linked to antibody polyspecificity. To better understand antibody affinity/specificity trade-offs, we have selected single-chain antibody fragments specific for the negatively charged and hydrophobic Alzheimer's amyloid β peptide using weak and stringent selections for antibody specificity. Antibody variants isolated using weak selections for specificity were enriched in arginine CDR mutations and displayed low specificity. Alanine-scanning mutagenesis revealed that the affinities of these antibodies were strongly dependent on their arginine mutations. Antibody variants isolated using stringent selections for specificity were also enriched in arginine CDR mutations, but these antibodies possessed significant improvements in specificity. Importantly, the affinities of the most specific antibodies were much less dependent on their arginine mutations, suggesting that over-reliance on arginine for affinity leads to reduced specificity. Structural modeling and molecular simulations reveal unique hydrophobic environments near the arginine CDR mutations. The more specific antibodies contained arginine mutations in the most hydrophobic portions of the CDRs, whereas the less specific antibodies contained arginine mutations in more hydrophilic regions. These findings demonstrate that arginine mutations in antibody CDRs display context-dependent impacts on specificity and that affinity/specificity trade-offs are governed by the relative contribution of arginine CDR residues to the overall antibody affinity.

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Inhibition of Aggregation of Amyloid β42 by Arginine-Containing Small Compounds

Cited by 25 publications

References 18 publications

α-Lactalbumin, Amazing Calcium-Binding Protein

α-Lactalbumin, Amazing Calcium-Binding Protein

Effect of Mid-infrared Free-Electron Laser Irradiation on Refolding of Amyloid-Like Fibrils of Lysozyme into Native Form

Arginine mutations in antibody complementarity-determining regions display context-dependent affinity/specificity trade-offs

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