MIA40 circumvents the folding constraints imposed by TRIAP1 function

Autores
Pujols, Jordi; Fornt Suñé, Marc; Gil García, Marcos; Bartolomé Nafría, Andrea; Canals, Francesc; Cerofolini, Linda; Teilum, Kaare; Banci, Lucia; Esperante, Sebastian; Ventura, Salvador
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The MIA40 relay system mediates the import of small cysteine-rich proteins into the intermembrane mitochondrial space (IMS). MIA40 substrates are synthesized in the cytosol and assumed to be disordered in their reduced state in this compartment. As they cross the outer mitochondrial membrane, MIA40 promotes the oxidation of critical native disulfides to facilitate folding, trapping functional species in the IMS. Here, we study the redox-controled folding of TRIAP1, a small cysteine-rich protein with moonlighting function: regulating phospholipid trafficking between mitochondrial membranes in the IMS and preventing apoptosis in the cytosol. TRIAP1 dysregulation is connected to oncogenesis. Although TRIAP1 contains a canonical twin CX9C motif, its sequence characteristics and folding pathway deviate from typical MIA40 substrates. In its reduced state, TRIAP1 rapidly populates a hydrophobic collapsed, alpha-helical, and marginally stable molten globule. This intermediate biases oxidative folding towards a non-native Cys37-Cys47 kinetic trap, slowing the reaction. MIA40 accelerates TRIAP1 folding rate by 30-fold, bypassing the formation of this folding trap. MIA40 drives the oxidation of the inner disulfide bond Cys18-Cys37, and subsequently, it can catalyze the formation of the outer disulfide bond Cys8-Cys47 to attain the native two-disulfide-bridged structure. We demonstrate that, unlike most MIA40 substrates, TRIAP1´s folding pathway is strongly constrained by the structural requirements for its function in phospholipid traffic at the IMS. The obligatory population of a reduced, alpha-helical, metastable molten globule in the cytoplasm may explain TRIAP1´s connection to the p53-dependent cell survival pathway, constituting a remarkable example of a functional molten globule state.
Fil: Pujols, Jordi. Universitat Autònoma de Barcelona; España
Fil: Fornt Suñé, Marc. Universitat Autònoma de Barcelona; España
Fil: Gil García, Marcos. Universitat Autònoma de Barcelona; España
Fil: Bartolomé Nafría, Andrea. Universitat Autònoma de Barcelona; España
Fil: Canals, Francesc. Institut d’Oncologia Vall d’Hebron; España
Fil: Cerofolini, Linda. University of Florence; Italia
Fil: Teilum, Kaare. Universidad de Copenhagen; Dinamarca
Fil: Banci, Lucia. University of Florence; Italia
Fil: Esperante, Sebastian. Universidad Nacional de San Martin. Centro de Rediseño E Ingenieria de Proteinas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
Materia
OXIDATIVE FOLDING
MOLTEN GLOBULE
TRIAP1
MIA CHAPERONE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/266478
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/266478
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling MIA40 circumvents the folding constraints imposed by TRIAP1 functionPujols, JordiFornt Suñé, MarcGil García, MarcosBartolomé Nafría, AndreaCanals, FrancescCerofolini, LindaTeilum, KaareBanci, LuciaEsperante, SebastianVentura, SalvadorOXIDATIVE FOLDINGMOLTEN GLOBULETRIAP1MIA CHAPERONEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The MIA40 relay system mediates the import of small cysteine-rich proteins into the intermembrane mitochondrial space (IMS). MIA40 substrates are synthesized in the cytosol and assumed to be disordered in their reduced state in this compartment. As they cross the outer mitochondrial membrane, MIA40 promotes the oxidation of critical native disulfides to facilitate folding, trapping functional species in the IMS. Here, we study the redox-controled folding of TRIAP1, a small cysteine-rich protein with moonlighting function: regulating phospholipid trafficking between mitochondrial membranes in the IMS and preventing apoptosis in the cytosol. TRIAP1 dysregulation is connected to oncogenesis. Although TRIAP1 contains a canonical twin CX9C motif, its sequence characteristics and folding pathway deviate from typical MIA40 substrates. In its reduced state, TRIAP1 rapidly populates a hydrophobic collapsed, alpha-helical, and marginally stable molten globule. This intermediate biases oxidative folding towards a non-native Cys37-Cys47 kinetic trap, slowing the reaction. MIA40 accelerates TRIAP1 folding rate by 30-fold, bypassing the formation of this folding trap. MIA40 drives the oxidation of the inner disulfide bond Cys18-Cys37, and subsequently, it can catalyze the formation of the outer disulfide bond Cys8-Cys47 to attain the native two-disulfide-bridged structure. We demonstrate that, unlike most MIA40 substrates, TRIAP1´s folding pathway is strongly constrained by the structural requirements for its function in phospholipid traffic at the IMS. The obligatory population of a reduced, alpha-helical, metastable molten globule in the cytoplasm may explain TRIAP1´s connection to the p53-dependent cell survival pathway, constituting a remarkable example of a functional molten globule state.Fil: Pujols, Jordi. Universitat Autònoma de Barcelona; EspañaFil: Fornt Suñé, Marc. Universitat Autònoma de Barcelona; EspañaFil: Gil García, Marcos. Universitat Autònoma de Barcelona; EspañaFil: Bartolomé Nafría, Andrea. Universitat Autònoma de Barcelona; EspañaFil: Canals, Francesc. Institut d’Oncologia Vall d’Hebron; EspañaFil: Cerofolini, Linda. University of Florence; ItaliaFil: Teilum, Kaare. Universidad de Copenhagen; DinamarcaFil: Banci, Lucia. University of Florence; ItaliaFil: Esperante, Sebastian. Universidad Nacional de San Martin. Centro de Rediseño E Ingenieria de Proteinas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ventura, Salvador. Universitat Autònoma de Barcelona; EspañaElsevier2025-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266478Pujols, Jordi; Fornt Suñé, Marc; Gil García, Marcos; Bartolomé Nafría, Andrea; Canals, Francesc; et al.; MIA40 circumvents the folding constraints imposed by TRIAP1 function; Elsevier; Journal of Biological Chemistry (online); 301; 3; 3-2025; 1-170021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0021925825001152info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2025.108268info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:40:22Zoai:ri.conicet.gov.ar:11336/266478instacron: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 10:40:22.378CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv MIA40 circumvents the folding constraints imposed by TRIAP1 function
title MIA40 circumvents the folding constraints imposed by TRIAP1 function
spellingShingle MIA40 circumvents the folding constraints imposed by TRIAP1 function
Pujols, Jordi
OXIDATIVE FOLDING
MOLTEN GLOBULE
TRIAP1
MIA CHAPERONE
title_short MIA40 circumvents the folding constraints imposed by TRIAP1 function
title_full MIA40 circumvents the folding constraints imposed by TRIAP1 function
title_fullStr MIA40 circumvents the folding constraints imposed by TRIAP1 function
title_full_unstemmed MIA40 circumvents the folding constraints imposed by TRIAP1 function
title_sort MIA40 circumvents the folding constraints imposed by TRIAP1 function
dc.creator.none.fl_str_mv Pujols, Jordi
Fornt Suñé, Marc
Gil García, Marcos
Bartolomé Nafría, Andrea
Canals, Francesc
Cerofolini, Linda
Teilum, Kaare
Banci, Lucia
Esperante, Sebastian
Ventura, Salvador
author Pujols, Jordi
author_facet Pujols, Jordi
Fornt Suñé, Marc
Gil García, Marcos
Bartolomé Nafría, Andrea
Canals, Francesc
Cerofolini, Linda
Teilum, Kaare
Banci, Lucia
Esperante, Sebastian
Ventura, Salvador
author_role author
author2 Fornt Suñé, Marc
Gil García, Marcos
Bartolomé Nafría, Andrea
Canals, Francesc
Cerofolini, Linda
Teilum, Kaare
Banci, Lucia
Esperante, Sebastian
Ventura, Salvador
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv OXIDATIVE FOLDING
MOLTEN GLOBULE
TRIAP1
MIA CHAPERONE
topic OXIDATIVE FOLDING
MOLTEN GLOBULE
TRIAP1
MIA CHAPERONE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The MIA40 relay system mediates the import of small cysteine-rich proteins into the intermembrane mitochondrial space (IMS). MIA40 substrates are synthesized in the cytosol and assumed to be disordered in their reduced state in this compartment. As they cross the outer mitochondrial membrane, MIA40 promotes the oxidation of critical native disulfides to facilitate folding, trapping functional species in the IMS. Here, we study the redox-controled folding of TRIAP1, a small cysteine-rich protein with moonlighting function: regulating phospholipid trafficking between mitochondrial membranes in the IMS and preventing apoptosis in the cytosol. TRIAP1 dysregulation is connected to oncogenesis. Although TRIAP1 contains a canonical twin CX9C motif, its sequence characteristics and folding pathway deviate from typical MIA40 substrates. In its reduced state, TRIAP1 rapidly populates a hydrophobic collapsed, alpha-helical, and marginally stable molten globule. This intermediate biases oxidative folding towards a non-native Cys37-Cys47 kinetic trap, slowing the reaction. MIA40 accelerates TRIAP1 folding rate by 30-fold, bypassing the formation of this folding trap. MIA40 drives the oxidation of the inner disulfide bond Cys18-Cys37, and subsequently, it can catalyze the formation of the outer disulfide bond Cys8-Cys47 to attain the native two-disulfide-bridged structure. We demonstrate that, unlike most MIA40 substrates, TRIAP1´s folding pathway is strongly constrained by the structural requirements for its function in phospholipid traffic at the IMS. The obligatory population of a reduced, alpha-helical, metastable molten globule in the cytoplasm may explain TRIAP1´s connection to the p53-dependent cell survival pathway, constituting a remarkable example of a functional molten globule state.
Fil: Pujols, Jordi. Universitat Autònoma de Barcelona; España
Fil: Fornt Suñé, Marc. Universitat Autònoma de Barcelona; España
Fil: Gil García, Marcos. Universitat Autònoma de Barcelona; España
Fil: Bartolomé Nafría, Andrea. Universitat Autònoma de Barcelona; España
Fil: Canals, Francesc. Institut d’Oncologia Vall d’Hebron; España
Fil: Cerofolini, Linda. University of Florence; Italia
Fil: Teilum, Kaare. Universidad de Copenhagen; Dinamarca
Fil: Banci, Lucia. University of Florence; Italia
Fil: Esperante, Sebastian. Universidad Nacional de San Martin. Centro de Rediseño E Ingenieria de Proteinas.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ventura, Salvador. Universitat Autònoma de Barcelona; España
description The MIA40 relay system mediates the import of small cysteine-rich proteins into the intermembrane mitochondrial space (IMS). MIA40 substrates are synthesized in the cytosol and assumed to be disordered in their reduced state in this compartment. As they cross the outer mitochondrial membrane, MIA40 promotes the oxidation of critical native disulfides to facilitate folding, trapping functional species in the IMS. Here, we study the redox-controled folding of TRIAP1, a small cysteine-rich protein with moonlighting function: regulating phospholipid trafficking between mitochondrial membranes in the IMS and preventing apoptosis in the cytosol. TRIAP1 dysregulation is connected to oncogenesis. Although TRIAP1 contains a canonical twin CX9C motif, its sequence characteristics and folding pathway deviate from typical MIA40 substrates. In its reduced state, TRIAP1 rapidly populates a hydrophobic collapsed, alpha-helical, and marginally stable molten globule. This intermediate biases oxidative folding towards a non-native Cys37-Cys47 kinetic trap, slowing the reaction. MIA40 accelerates TRIAP1 folding rate by 30-fold, bypassing the formation of this folding trap. MIA40 drives the oxidation of the inner disulfide bond Cys18-Cys37, and subsequently, it can catalyze the formation of the outer disulfide bond Cys8-Cys47 to attain the native two-disulfide-bridged structure. We demonstrate that, unlike most MIA40 substrates, TRIAP1´s folding pathway is strongly constrained by the structural requirements for its function in phospholipid traffic at the IMS. The obligatory population of a reduced, alpha-helical, metastable molten globule in the cytoplasm may explain TRIAP1´s connection to the p53-dependent cell survival pathway, constituting a remarkable example of a functional molten globule state.
publishDate 2025
dc.date.none.fl_str_mv 2025-03
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/11336/266478
Pujols, Jordi; Fornt Suñé, Marc; Gil García, Marcos; Bartolomé Nafría, Andrea; Canals, Francesc; et al.; MIA40 circumvents the folding constraints imposed by TRIAP1 function; Elsevier; Journal of Biological Chemistry (online); 301; 3; 3-2025; 1-17
0021-9258
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266478
identifier_str_mv Pujols, Jordi; Fornt Suñé, Marc; Gil García, Marcos; Bartolomé Nafría, Andrea; Canals, Francesc; et al.; MIA40 circumvents the folding constraints imposed by TRIAP1 function; Elsevier; Journal of Biological Chemistry (online); 301; 3; 3-2025; 1-17
0021-9258
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0021925825001152
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jbc.2025.108268
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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