Complex Energy Landscape of a Giant Repeat Protein

Autores
Tsytlonok, Maksym; Craig, Patricio Oliver; Sivertsson, Elin; Serquera, David; Perrett, Sarah; Best, Robert B.; Wolynes, Peter G.; Itzhaki, Laura S.
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Here, we reveal a remarkable complexity in the unfolding of giant HEAT-repeat protein PR65/A, a molecular adaptor for the heterotrimeric PP2A phosphatases. The repeat array ruptures at multiple sites, leading to intermediate states with noncontiguous folded subdomains. There is a dominant sequence of unfolding, which reflects a nonuniform stability distribution across the repeat array and can be rationalized by theoretical models accounting for heterogeneous contact density in the folded structure. Unfolding of certain intermediates is, however, competitive, leading to parallel unfolding pathways. The low-stability, central repeats sample unfolded conformations under physiological conditions, suggesting how folding directs function: certain regions present rigid motifs for molecular recognition, whereas others have the flexibility with which to broaden the search area, as in the fly-casting mechanism. Partial unfolding of PR65/A also impacts catalysis by altering the proximity of bound catalytic subunit and substrate. Thus, the repeat array orchestrates the assembly and activity of PP2A.
Fil: Tsytlonok, Maksym. University Of Cambridge; Estados Unidos. Hutchison/MRC Research Centre; Reino Unido
Fil: Craig, Patricio Oliver. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. University Of California At San Diego; Estados Unidos
Fil: Sivertsson, Elin. University Of Cambridge; Reino Unido
Fil: Serquera, David. Hutchison/MRC Research Centre; Reino Unido
Fil: Perrett, Sarah. Chinese Academy Of Sciences; República de China
Fil: Best, Robert B.. University Of Cambridge; Reino Unido
Fil: Wolynes, Peter G.. Rice University; Estados Unidos
Fil: Itzhaki, Laura S.. University Of Cambridge; Reino Unido
Materia
Heat Repeat
Folding Mechanism
Pr65
Molecular Simulation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/7694
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/7694
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Complex Energy Landscape of a Giant Repeat ProteinTsytlonok, MaksymCraig, Patricio OliverSivertsson, ElinSerquera, DavidPerrett, SarahBest, Robert B.Wolynes, Peter G.Itzhaki, Laura S.Heat RepeatFolding MechanismPr65Molecular Simulationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Here, we reveal a remarkable complexity in the unfolding of giant HEAT-repeat protein PR65/A, a molecular adaptor for the heterotrimeric PP2A phosphatases. The repeat array ruptures at multiple sites, leading to intermediate states with noncontiguous folded subdomains. There is a dominant sequence of unfolding, which reflects a nonuniform stability distribution across the repeat array and can be rationalized by theoretical models accounting for heterogeneous contact density in the folded structure. Unfolding of certain intermediates is, however, competitive, leading to parallel unfolding pathways. The low-stability, central repeats sample unfolded conformations under physiological conditions, suggesting how folding directs function: certain regions present rigid motifs for molecular recognition, whereas others have the flexibility with which to broaden the search area, as in the fly-casting mechanism. Partial unfolding of PR65/A also impacts catalysis by altering the proximity of bound catalytic subunit and substrate. Thus, the repeat array orchestrates the assembly and activity of PP2A.Fil: Tsytlonok, Maksym. University Of Cambridge; Estados Unidos. Hutchison/MRC Research Centre; Reino UnidoFil: Craig, Patricio Oliver. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. University Of California At San Diego; Estados UnidosFil: Sivertsson, Elin. University Of Cambridge; Reino UnidoFil: Serquera, David. Hutchison/MRC Research Centre; Reino UnidoFil: Perrett, Sarah. Chinese Academy Of Sciences; República de ChinaFil: Best, Robert B.. University Of Cambridge; Reino UnidoFil: Wolynes, Peter G.. Rice University; Estados UnidosFil: Itzhaki, Laura S.. University Of Cambridge; Reino UnidoCell Press2013-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/7694Tsytlonok, Maksym; Craig, Patricio Oliver; Sivertsson, Elin; Serquera, David; Perrett, Sarah; et al.; Complex Energy Landscape of a Giant Repeat Protein; Cell Press; Structure With Folding & Design.; 21; 11; 11-2013; 1954-19650969-2126enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S096921261300350Xinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.str.2013.08.028info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:39:08Zoai:ri.conicet.gov.ar:11336/7694instacron: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:34982025-09-29 09:39:09.271CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Complex Energy Landscape of a Giant Repeat Protein
title Complex Energy Landscape of a Giant Repeat Protein
spellingShingle Complex Energy Landscape of a Giant Repeat Protein
Tsytlonok, Maksym
Heat Repeat
Folding Mechanism
Pr65
Molecular Simulation
title_short Complex Energy Landscape of a Giant Repeat Protein
title_full Complex Energy Landscape of a Giant Repeat Protein
title_fullStr Complex Energy Landscape of a Giant Repeat Protein
title_full_unstemmed Complex Energy Landscape of a Giant Repeat Protein
title_sort Complex Energy Landscape of a Giant Repeat Protein
dc.creator.none.fl_str_mv Tsytlonok, Maksym
Craig, Patricio Oliver
Sivertsson, Elin
Serquera, David
Perrett, Sarah
Best, Robert B.
Wolynes, Peter G.
Itzhaki, Laura S.
author Tsytlonok, Maksym
author_facet Tsytlonok, Maksym
Craig, Patricio Oliver
Sivertsson, Elin
Serquera, David
Perrett, Sarah
Best, Robert B.
Wolynes, Peter G.
Itzhaki, Laura S.
author_role author
author2 Craig, Patricio Oliver
Sivertsson, Elin
Serquera, David
Perrett, Sarah
Best, Robert B.
Wolynes, Peter G.
Itzhaki, Laura S.
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Heat Repeat
Folding Mechanism
Pr65
Molecular Simulation
topic Heat Repeat
Folding Mechanism
Pr65
Molecular Simulation
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Here, we reveal a remarkable complexity in the unfolding of giant HEAT-repeat protein PR65/A, a molecular adaptor for the heterotrimeric PP2A phosphatases. The repeat array ruptures at multiple sites, leading to intermediate states with noncontiguous folded subdomains. There is a dominant sequence of unfolding, which reflects a nonuniform stability distribution across the repeat array and can be rationalized by theoretical models accounting for heterogeneous contact density in the folded structure. Unfolding of certain intermediates is, however, competitive, leading to parallel unfolding pathways. The low-stability, central repeats sample unfolded conformations under physiological conditions, suggesting how folding directs function: certain regions present rigid motifs for molecular recognition, whereas others have the flexibility with which to broaden the search area, as in the fly-casting mechanism. Partial unfolding of PR65/A also impacts catalysis by altering the proximity of bound catalytic subunit and substrate. Thus, the repeat array orchestrates the assembly and activity of PP2A.
Fil: Tsytlonok, Maksym. University Of Cambridge; Estados Unidos. Hutchison/MRC Research Centre; Reino Unido
Fil: Craig, Patricio Oliver. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. University Of California At San Diego; Estados Unidos
Fil: Sivertsson, Elin. University Of Cambridge; Reino Unido
Fil: Serquera, David. Hutchison/MRC Research Centre; Reino Unido
Fil: Perrett, Sarah. Chinese Academy Of Sciences; República de China
Fil: Best, Robert B.. University Of Cambridge; Reino Unido
Fil: Wolynes, Peter G.. Rice University; Estados Unidos
Fil: Itzhaki, Laura S.. University Of Cambridge; Reino Unido
description Here, we reveal a remarkable complexity in the unfolding of giant HEAT-repeat protein PR65/A, a molecular adaptor for the heterotrimeric PP2A phosphatases. The repeat array ruptures at multiple sites, leading to intermediate states with noncontiguous folded subdomains. There is a dominant sequence of unfolding, which reflects a nonuniform stability distribution across the repeat array and can be rationalized by theoretical models accounting for heterogeneous contact density in the folded structure. Unfolding of certain intermediates is, however, competitive, leading to parallel unfolding pathways. The low-stability, central repeats sample unfolded conformations under physiological conditions, suggesting how folding directs function: certain regions present rigid motifs for molecular recognition, whereas others have the flexibility with which to broaden the search area, as in the fly-casting mechanism. Partial unfolding of PR65/A also impacts catalysis by altering the proximity of bound catalytic subunit and substrate. Thus, the repeat array orchestrates the assembly and activity of PP2A.
publishDate 2013
dc.date.none.fl_str_mv 2013-11
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/11336/7694
Tsytlonok, Maksym; Craig, Patricio Oliver; Sivertsson, Elin; Serquera, David; Perrett, Sarah; et al.; Complex Energy Landscape of a Giant Repeat Protein; Cell Press; Structure With Folding & Design.; 21; 11; 11-2013; 1954-1965
0969-2126
url http://hdl.handle.net/11336/7694
identifier_str_mv Tsytlonok, Maksym; Craig, Patricio Oliver; Sivertsson, Elin; Serquera, David; Perrett, Sarah; et al.; Complex Energy Landscape of a Giant Repeat Protein; Cell Press; Structure With Folding & Design.; 21; 11; 11-2013; 1954-1965
0969-2126
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S096921261300350X
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.str.2013.08.028
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
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
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
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score 13.070432

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