Structural analysis of a natural apolipoprotein A-I variant (L60R) associated with amyloidosis

Gaddi, Gisela M.; Gisonno, Romina A.; Rosu, Silvana Antonia; Curto, Lucrecia María; Prieto, Eduardo; Schinella, Guillermo Raúl; Finarelli, Gabriela S.; Cortez, M. Fernanda; Bauzá, Letizia; Elías, Esteban Enrique; Ramella, Nahuel A.; Tricerri, M. Alejandra

doi:10.1016/j.abb.2020.108347

Cited by 9 publications

(3 citation statements)

References 57 publications

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“…In addition it is appropriate for evaluating protein catabolism, as it is exemplified here by the evidence with metalloproteinase 12 (MMP-12), which is a physiological protease that may elicit the pro-inflammatory processing of this variant within the lesions. We support the work “Structural analysis of a natural apolipoprotein A-I variant (L60R) associated with amyloidosis” (Gaddi, et al., 2020), gaining insights on protein folding from a characterization by proteolysis analysis [1] .…”

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confidence: 74%

Data regarding the sensibility to proteolysis of a natural apolipoprotein A-I mutant.

et al. 2020

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The article shows dataset of the proteolysis of a natural variant of apolipoprotein A-I (apoA-I) with a substitution of a leucine by and arginine in position 60 (L60R), in comparison with the protein with the native sequence (Wt). This information demonstrates the potential of in vitro partial proteolysis experiments as it may be applicable to different approaches in the biophysical field. We have analyzed by different electrophoresis techniques apoA-I variants, quantified the degree of proteolysis after staining and compared the proteolysis efficiency with the computed cleavage patterns. The data shown here clearly strengthen the usefulness of this approach to test protein flexibility, as it may be attained with enzymes which are not expected to modify in vivo this protein but have a well-known digestion pattern. In addition it is appropriate for evaluating protein catabolism, as it is exemplified here by the evidence with metalloproteinase 12 (MMP-12), which is a physiological protease that may elicit the pro-inflammatory processing of this variant within the lesions. We support the work “Structural analysis of a natural apolipoprotein A-I variant (L60R) associated with amyloidosis” (Gaddi, et al., 2020), gaining insights on protein folding from a characterization by proteolysis analysis [1] .

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confidence: 74%

Data regarding the sensibility to proteolysis of a natural apolipoprotein A-I mutant.

et al. 2020

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“…To complement our previous results showing the destabilizing effect of amyloid variants, we decided to study the dynamic properties of apoA-I amyloid mutants by conducting coarse-grain molecular dynamics simulations under the SIRAH force field. We selected four amyloid mutants (G26R, L60R, Δ107 and R173P) previously characterized by our group (21)(22)(23)(24), plus the wild type protein, to prepare our simulation systems. Our selection also ensured that mutations were distributed throughout the apoA-I sequence.…”

Section: Molecular Dynamics Simulations Of Apoa-i Mutantsmentioning

confidence: 99%

Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

et al. 2021

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Aggregation-prone region 1 (APR1), comprising residues 14-19, is consistently conserved during the evolutionary history of Apolipoprotein A-I. • APR1 contributes to thermal stability of the ɑ-helix bundle in the full-length Apolipoprotein A-I model. • Amyloid variants introduce a destabilizing effect on the monomer structure of Apolipoprotein A-I, in contrast to HDL-deficiency and naturally-occurring variants, which are nearly neutral. • During molecular dynamics simulations, G26R amyloidogenic mutant lead to the partial unfolding of ɑ-helix bundle and exposure of APR1..

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“…Such conformational flexibility of apoA‐I is also likely to be associated with its strong amyloidogenic propensity [17,18]. Conformational destabilization of apoA‐I caused by oxidation [19,20] or point mutations [21–24] is known to induce amyloid fibril formation by apoA‐I. The oxidation of non‐variant apoA‐I can cause acquired amyloidosis [19,20], whereas apoA‐I mutations can cause hereditary amyloidosis [25–27].…”

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confidence: 99%

Novel conformation‐selective monoclonal antibodies against apoA‐I amyloid fibrils

et al. 2020

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The N‐terminal 1–83 fragment of human apolipoprotein A‐I (apoA‐I) carrying G26R mutation forms amyloid fibrils that potentially cause hereditary amyloidosis. We generated monoclonal antibodies that specifically bind to amyloid fibrils composed of not only apoA‐I fragment but also α‐synuclein. In silico modeling suggests that the antibodies might recognize the characteristic quaternary structures, constructed due to parallel stacking of VYV (in apoA‐I fragment) or LYV (in α‐synuclein) motifs.

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Structural analysis of a natural apolipoprotein A-I variant (L60R) associated with amyloidosis

Cited by 9 publications

References 57 publications

Data regarding the sensibility to proteolysis of a natural apolipoprotein A-I mutant.

Data regarding the sensibility to proteolysis of a natural apolipoprotein A-I mutant.

Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior

Novel conformation‐selective monoclonal antibodies against apoA‐I amyloid fibrils

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