The allosteric modulation of thyroxine-binding globulin affinity is entropy driven

Background: Thyroxine-binding globulin (TBG) is a non-inhibitory member of the serpin family of proteins whose main structural element is the reactive center loop (RCL), that, upon cleavage by proteases, is inserted into the protein core adopting a β-strand conformation (stressed to relaxed transiti...

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Detalhes bibliográficos
Autores: Petruk, Ariel Alcides, Labanda, María Soledad, Alvarez, Rosa Maria Susana, Marti, Marcelo Adrian
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:Argentina
Recursos:Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio:CONICET Digital (CONICET)
Idioma:inglés
OAI Identifier:oai:ri.conicet.gov.ar:11336/22014
Acesso em linha:http://hdl.handle.net/11336/22014
Access Level:acceso abierto
Palavra-chave:Thyroxine-Binding Globulin
Serpin Family
Conformational Entropy
Molecular Dynamics
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
id AR_67ddf3fc51de5ddc641be4e2ef1113b6
oai_identifier_str oai:ri.conicet.gov.ar:11336/22014
network_acronym_str AR
network_name_str Argentina
repository_id_str
dc.title.none.fl_str_mv The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
title The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
spellingShingle The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
Petruk, Ariel Alcides
Thyroxine-Binding Globulin
Serpin Family
Conformational Entropy
Molecular Dynamics
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
title_short The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
title_full The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
title_fullStr The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
title_full_unstemmed The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
title_sort The allosteric modulation of thyroxine-binding globulin affinity is entropy driven
dc.creator.none.fl_str_mv Petruk, Ariel Alcides
Labanda, María Soledad
Alvarez, Rosa Maria Susana
Marti, Marcelo Adrian
author Petruk, Ariel Alcides
author_facet Petruk, Ariel Alcides
Labanda, María Soledad
Alvarez, Rosa Maria Susana
Marti, Marcelo Adrian
author_role author
author2 Labanda, María Soledad
Alvarez, Rosa Maria Susana
Marti, Marcelo Adrian
author2_role author
author
author
dc.subject.none.fl_str_mv Thyroxine-Binding Globulin
Serpin Family
Conformational Entropy
Molecular Dynamics
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
topic Thyroxine-Binding Globulin
Serpin Family
Conformational Entropy
Molecular Dynamics
https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
description Background: Thyroxine-binding globulin (TBG) is a non-inhibitory member of the serpin family of proteins whose main structural element is the reactive center loop (RCL), that, upon cleavage by proteases, is inserted into the protein core adopting a β-strand conformation (stressed to relaxed transition, S-to-R). After S-to-R transition thyroxine (T4) affinity decreases. However, crystallographic studies in the presence or absence of the hormone in different states are unable to show significant differences in the structure and interactions of the binding site. Experimental results also suggest the existence of several S states (differing in the number of inserted RCL residues), associated with a differential affinity. Methods: To shed light into the molecular basis that regulates T4 affinity according to the degree of RCL insertion in TBG, we performed extended molecular dynamics simulations combined with several thermodynamic analysis of the T4 binding to TBG in three different S states, and in the R state. Results: Our results show that, despite T4 binding in the protein by similar interactions in all states, a good correlation between the degree of RCL insertion and the binding affinity, driven by a change in TBG conformational entropy, was observed. Conclusion: TBG allosteric regulation is entropy driven. The presence of multiple S states may allow more efficient T4 release due to protease activity. General significance: The presented results are clear examples of how computer simulation methods can reveal the thermodynamic basis of allosteric effects, and provide a general framework for understanding serpin allosteric affinity regulation.
publishDate 2013
dc.date.none.fl_str_mv 2013-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/22014
Petruk, Ariel Alcides; Labanda, María Soledad; Alvarez, Rosa Maria Susana; Marti, Marcelo Adrian; The allosteric modulation of thyroxine-binding globulin affinity is entropy driven; Elsevier Science; Biochimica Et Biophysica Acta- General Subjects; 1830; 6; 3-2013; 3570-3577
0304-4165
CONICET Digital
CONICET
url http://hdl.handle.net/11336/22014
identifier_str_mv Petruk, Ariel Alcides; Labanda, María Soledad; Alvarez, Rosa Maria Susana; Marti, Marcelo Adrian; The allosteric modulation of thyroxine-binding globulin affinity is entropy driven; Elsevier Science; Biochimica Et Biophysica Acta- General Subjects; 1830; 6; 3-2013; 3570-3577
0304-4165
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2013.02.023
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0304416513000743
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science
publisher.none.fl_str_mv Elsevier Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1799195307053940736
spelling The allosteric modulation of thyroxine-binding globulin affinity is entropy drivenPetruk, Ariel AlcidesLabanda, María SoledadAlvarez, Rosa Maria SusanaMarti, Marcelo AdrianThyroxine-Binding GlobulinSerpin FamilyConformational EntropyMolecular Dynamicshttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background: Thyroxine-binding globulin (TBG) is a non-inhibitory member of the serpin family of proteins whose main structural element is the reactive center loop (RCL), that, upon cleavage by proteases, is inserted into the protein core adopting a β-strand conformation (stressed to relaxed transition, S-to-R). After S-to-R transition thyroxine (T4) affinity decreases. However, crystallographic studies in the presence or absence of the hormone in different states are unable to show significant differences in the structure and interactions of the binding site. Experimental results also suggest the existence of several S states (differing in the number of inserted RCL residues), associated with a differential affinity. Methods: To shed light into the molecular basis that regulates T4 affinity according to the degree of RCL insertion in TBG, we performed extended molecular dynamics simulations combined with several thermodynamic analysis of the T4 binding to TBG in three different S states, and in the R state. Results: Our results show that, despite T4 binding in the protein by similar interactions in all states, a good correlation between the degree of RCL insertion and the binding affinity, driven by a change in TBG conformational entropy, was observed. Conclusion: TBG allosteric regulation is entropy driven. The presence of multiple S states may allow more efficient T4 release due to protease activity. General significance: The presented results are clear examples of how computer simulation methods can reveal the thermodynamic basis of allosteric effects, and provide a general framework for understanding serpin allosteric affinity regulation.Fil: Petruk, Ariel Alcides. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucuman. Instituto Superior de Investigaciones Biologicas; ArgentinaFil: Labanda, María Soledad. Universidad Nacional de Tucuman. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alvarez, Rosa Maria Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucuman. Instituto Superior de Investigaciones Biologicas; Argentina. Universidad Nacional de Tucuman. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Física; ArgentinaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; ArgentinaElsevier Science2013-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/22014Petruk, Ariel Alcides; Labanda, María Soledad; Alvarez, Rosa Maria Susana; Marti, Marcelo Adrian; The allosteric modulation of thyroxine-binding globulin affinity is entropy driven; Elsevier Science; Biochimica Et Biophysica Acta- General Subjects; 1830; 6; 3-2013; 3570-35770304-4165CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbagen.2013.02.023info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0304416513000743info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2024-05-08T13:48:39Zoai:ri.conicet.gov.ar:11336/22014instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982024-05-08 13:48:40.166CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
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