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dc.contributor.author
Meini, María Rocío
dc.contributor.author
Tomatis, Pablo Emiliano
dc.contributor.author
Weinreich, Daniel M.
dc.contributor.author
Vila, Alejandro Jose
dc.date.available
2017-07-26T19:15:25Z
dc.date.issued
2015-03
dc.identifier.citation
Meini, María Rocío; Tomatis, Pablo Emiliano; Weinreich, Daniel M.; Vila, Alejandro Jose; Quantitative Description of a Protein Fitness Landscape Based on Molecular Features; Oxford University Press; Molecular Biology And Evolution; 32; 7; 3-2015; 1774-1787
dc.identifier.issn
0737-4038
dc.identifier.uri
http://hdl.handle.net/11336/21363
dc.description.abstract
Understanding the driving forces behind protein evolution requires the ability to correlate the molecular impact of mutations with organismal fitness. To address this issue, we employ here metallo--lactamases as a model system, which are Zn(II) dependent enzymes that mediate antibiotic resistance. We present a study of all the possible evolutionary pathways leading to a metallo--lactamase variant optimized by directed evolution. By studying the activity, stability and Zn(II) binding capabilities of all mutants in the preferred evolutionary pathways, we show that this local fitness landscape is strongly conditioned by epistatic interactions arising from the pleiotropic effect of mutations in the different molecular features of the enzyme. Activity and stability assays in purified enzymes do not provide explanatory power. Instead, measurement of these molecular features in an environment resembling the native one provides an accurate description of the observed antibiotic resistance profile. We report that optimization of Zn(II) binding abilities of metallo--lactamases during evolution is more critical than stabilization of the protein to enhance fitness. A global analysis of these parameters allows us to connect genotype with fitness based on quantitative biochemical and biophysical parameters.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford University Press
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Antibiotic Resistance
dc.subject
Epistasis
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Metallo-ß-Lactamase
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Protein Evolution
dc.subject.classification
Biofísica
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Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
dc.title
Quantitative Description of a Protein Fitness Landscape Based on Molecular Features
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-11-24T19:36:57Z
dc.journal.volume
32
dc.journal.number
7
dc.journal.pagination
1774-1787
dc.journal.pais
Reino Unido
dc.journal.ciudad
Oxford
dc.description.fil
Fil: Meini, María Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil
Fil: Tomatis, Pablo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil
Fil: Weinreich, Daniel M.. University Brown; Estados Unidos
dc.description.fil
Fil: Vila, Alejandro Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.journal.title
Molecular Biology And Evolution
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1093/molbev/msv059
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/mbe/article-lookup/doi/10.1093/molbev/msv059


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    Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO

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