Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?

Autores
Díaz Ludovico, Ivo; Gisonno, Romina Antonela; González, Marina Cecilia; Garda, Horacio Alberto; Ramella, Nahuel Alberto; Tricerri, María Alejandra
Año de publicación
2021
Idioma
español castellano
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis. Methods: Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in native conformation or under oxidation or intramolecular crosslinking. Results: K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants. Conclusions: We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoAI modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency. General significance: The results learnt from this variant strength a close association between amyloidosis and atherosclerosis.
Instituto de Investigaciones Bioquímicas de La Plata
Facultad de Ciencias Médicas
Materia
Ciencias Médicas
Atherosclerosis
Apolipoprotein A-I
K107del natural variant
Protein misfolding
Amyloidosis
Inflammation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
http://creativecommons.org/licenses/by-nc-nd/4.0/
Repositorio
SEDICI (UNLP)
Institución
Universidad Nacional de La Plata
OAI Identificador
oai:sedici.unlp.edu.ar:10915/124995

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spelling Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?Díaz Ludovico, IvoGisonno, Romina AntonelaGonzález, Marina CeciliaGarda, Horacio AlbertoRamella, Nahuel AlbertoTricerri, María AlejandraCiencias MédicasAtherosclerosisApolipoprotein A-IK107del natural variantProtein misfoldingAmyloidosisInflammationBackground: The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis. Methods: Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in native conformation or under oxidation or intramolecular crosslinking. Results: K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants. Conclusions: We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoAI modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency. General significance: The results learnt from this variant strength a close association between amyloidosis and atherosclerosis.Instituto de Investigaciones Bioquímicas de La PlataFacultad de Ciencias Médicas2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://sedici.unlp.edu.ar/handle/10915/124995spainfo:eu-repo/semantics/altIdentifier/issn/0304-4165/info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2020.129732info:eu-repo/semantics/reference/hdl/10915/124884info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0/Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)reponame:SEDICI (UNLP)instname:Universidad Nacional de La Platainstacron:UNLP2025-10-15T11:21:57Zoai:sedici.unlp.edu.ar:10915/124995Institucionalhttp://sedici.unlp.edu.ar/Universidad públicaNo correspondehttp://sedici.unlp.edu.ar/oai/snrdalira@sedici.unlp.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:13292025-10-15 11:21:57.54SEDICI (UNLP) - Universidad Nacional de La Platafalse
dc.title.none.fl_str_mv Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
title Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
spellingShingle Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
Díaz Ludovico, Ivo
Ciencias Médicas
Atherosclerosis
Apolipoprotein A-I
K107del natural variant
Protein misfolding
Amyloidosis
Inflammation
title_short Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
title_full Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
title_fullStr Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
title_full_unstemmed Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
title_sort Understanding the role of apolipoproteinA-I in atherosclerosis : Posttranslational modifications synergize dysfunction?
dc.creator.none.fl_str_mv Díaz Ludovico, Ivo
Gisonno, Romina Antonela
González, Marina Cecilia
Garda, Horacio Alberto
Ramella, Nahuel Alberto
Tricerri, María Alejandra
author Díaz Ludovico, Ivo
author_facet Díaz Ludovico, Ivo
Gisonno, Romina Antonela
González, Marina Cecilia
Garda, Horacio Alberto
Ramella, Nahuel Alberto
Tricerri, María Alejandra
author_role author
author2 Gisonno, Romina Antonela
González, Marina Cecilia
Garda, Horacio Alberto
Ramella, Nahuel Alberto
Tricerri, María Alejandra
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Ciencias Médicas
Atherosclerosis
Apolipoprotein A-I
K107del natural variant
Protein misfolding
Amyloidosis
Inflammation
topic Ciencias Médicas
Atherosclerosis
Apolipoprotein A-I
K107del natural variant
Protein misfolding
Amyloidosis
Inflammation
dc.description.none.fl_txt_mv Background: The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis. Methods: Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in native conformation or under oxidation or intramolecular crosslinking. Results: K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants. Conclusions: We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoAI modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency. General significance: The results learnt from this variant strength a close association between amyloidosis and atherosclerosis.
Instituto de Investigaciones Bioquímicas de La Plata
Facultad de Ciencias Médicas
description Background: The identification of dysfunctional human apolipoprotein A-I (apoA-I) in atherosclerotic plaques suggests that protein structure and function may be hampered under a chronic pro inflammatory scenario. Moreover, the fact that natural mutants of this protein elicit severe cardiovascular diseases (CVD) strongly indicates that the native folding could shift due to the mutation, yielding a structure more prone to misfold or misfunction. To understand the events that determine the failure of apoA-I structural flexibility to fulfill its protective role, we took advantage of the study of a natural variant with a deletion of the residue lysine 107 (K107del) associated with atherosclerosis. Methods: Biophysical approaches, such as electrophoresis, fluorescence and spectroscopy were used to characterize proteins structure and function, either in native conformation or under oxidation or intramolecular crosslinking. Results: K107del structure was more flexible than the protein with the native sequence (Wt) but interactions with artificial membranes were preserved. Instead, structural restrictions by intramolecular crosslinking impaired the Wt and K107del lipid solubilization function. In addition, controlled oxidation decreased the yield of the native dimer conformation for both variants. Conclusions: We conclude that even though mutations may alter protein structure and spatial arrangement, the highly flexible conformation compensates the mild shift from the native folding. Instead, post translational apoAI modifications (probably chronic and progressive) are required to raise a protein conformation with significant loss of function and increased aggregation tendency. General significance: The results learnt from this variant strength a close association between amyloidosis and atherosclerosis.
publishDate 2021
dc.date.none.fl_str_mv 2021
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info:eu-repo/semantics/publishedVersion
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2020.129732
info:eu-repo/semantics/reference/hdl/10915/124884
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by-nc-nd/4.0/
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
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rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
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