Molecular basis of Tousled-Like Kinase 2 activation

Autores
Mortuza, Gulnahar B.; Hermida, Dario; Pedersen, Anna-Kathrine; Segura-Bayona, Sandra; López-Méndez, Blanca; Redondo, Pilar; Rüther, Patrick; Pozdnyakova, Irina; Garrote López, Ana Marcela; Muñoz, Inés G.; Villamor-Payà, Marina; Jauset, Cristina; Olsen, Jesper V.; Stracker, Travis H.; Montoya, Guillermo
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.
Fil: Mortuza, Gulnahar B.. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Hermida, Dario. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Pedersen, Anna-Kathrine. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Segura-Bayona, Sandra. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: López-Méndez, Blanca. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Redondo, Pilar. Centro Nacional de Investigaciones Oncológicas; España
Fil: Rüther, Patrick. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Pozdnyakova, Irina. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Garrote López, Ana Marcela. Centro Nacional de Investigaciones Oncológicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Muñoz, Inés G.. Centro Nacional de Investigaciones Oncológicas; España
Fil: Villamor-Payà, Marina. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Jauset, Cristina. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Olsen, Jesper V.. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Stracker, Travis H.. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Montoya, Guillermo. Faculty Of Health And Medical Sciences; Dinamarca
Materia
TLK
chromatine structure
kinase activity
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/210686
Acceder
id CONICETDig_0cd1ead1256c2980e4c7a5a89921fb87
oai_identifier_str oai:ri.conicet.gov.ar:11336/210686
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular basis of Tousled-Like Kinase 2 activationMortuza, Gulnahar B.Hermida, DarioPedersen, Anna-KathrineSegura-Bayona, SandraLópez-Méndez, BlancaRedondo, PilarRüther, PatrickPozdnyakova, IrinaGarrote López, Ana MarcelaMuñoz, Inés G.Villamor-Payà, MarinaJauset, CristinaOlsen, Jesper V.Stracker, Travis H.Montoya, GuillermoTLKchromatine structurekinase activityhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.Fil: Mortuza, Gulnahar B.. Faculty Of Health And Medical Sciences; DinamarcaFil: Hermida, Dario. Faculty Of Health And Medical Sciences; DinamarcaFil: Pedersen, Anna-Kathrine. Faculty Of Health And Medical Sciences; DinamarcaFil: Segura-Bayona, Sandra. Irb Barcelona - Institute For Research In Biomedicine; EspañaFil: López-Méndez, Blanca. Faculty Of Health And Medical Sciences; DinamarcaFil: Redondo, Pilar. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Rüther, Patrick. Faculty Of Health And Medical Sciences; DinamarcaFil: Pozdnyakova, Irina. Faculty Of Health And Medical Sciences; DinamarcaFil: Garrote López, Ana Marcela. Centro Nacional de Investigaciones Oncológicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; ArgentinaFil: Muñoz, Inés G.. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Villamor-Payà, Marina. Irb Barcelona - Institute For Research In Biomedicine; EspañaFil: Jauset, Cristina. Irb Barcelona - Institute For Research In Biomedicine; EspañaFil: Olsen, Jesper V.. Faculty Of Health And Medical Sciences; DinamarcaFil: Stracker, Travis H.. Irb Barcelona - Institute For Research In Biomedicine; EspañaFil: Montoya, Guillermo. Faculty Of Health And Medical Sciences; DinamarcaNature Publishing Group2018-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/210686Mortuza, Gulnahar B.; Hermida, Dario; Pedersen, Anna-Kathrine; Segura-Bayona, Sandra; López-Méndez, Blanca; et al.; Molecular basis of Tousled-Like Kinase 2 activation; Nature Publishing Group; Nature Communications; 9; 1; 12-20182041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-018-04941-yinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:45:06Zoai:ri.conicet.gov.ar:11336/210686instacron: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 09:45:06.692CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular basis of Tousled-Like Kinase 2 activation
title Molecular basis of Tousled-Like Kinase 2 activation
spellingShingle Molecular basis of Tousled-Like Kinase 2 activation
Mortuza, Gulnahar B.
TLK
chromatine structure
kinase activity
title_short Molecular basis of Tousled-Like Kinase 2 activation
title_full Molecular basis of Tousled-Like Kinase 2 activation
title_fullStr Molecular basis of Tousled-Like Kinase 2 activation
title_full_unstemmed Molecular basis of Tousled-Like Kinase 2 activation
title_sort Molecular basis of Tousled-Like Kinase 2 activation
dc.creator.none.fl_str_mv Mortuza, Gulnahar B.
Hermida, Dario
Pedersen, Anna-Kathrine
Segura-Bayona, Sandra
López-Méndez, Blanca
Redondo, Pilar
Rüther, Patrick
Pozdnyakova, Irina
Garrote López, Ana Marcela
Muñoz, Inés G.
Villamor-Payà, Marina
Jauset, Cristina
Olsen, Jesper V.
Stracker, Travis H.
Montoya, Guillermo
author Mortuza, Gulnahar B.
author_facet Mortuza, Gulnahar B.
Hermida, Dario
Pedersen, Anna-Kathrine
Segura-Bayona, Sandra
López-Méndez, Blanca
Redondo, Pilar
Rüther, Patrick
Pozdnyakova, Irina
Garrote López, Ana Marcela
Muñoz, Inés G.
Villamor-Payà, Marina
Jauset, Cristina
Olsen, Jesper V.
Stracker, Travis H.
Montoya, Guillermo
author_role author
author2 Hermida, Dario
Pedersen, Anna-Kathrine
Segura-Bayona, Sandra
López-Méndez, Blanca
Redondo, Pilar
Rüther, Patrick
Pozdnyakova, Irina
Garrote López, Ana Marcela
Muñoz, Inés G.
Villamor-Payà, Marina
Jauset, Cristina
Olsen, Jesper V.
Stracker, Travis H.
Montoya, Guillermo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TLK
chromatine structure
kinase activity
topic TLK
chromatine structure
kinase activity
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.
Fil: Mortuza, Gulnahar B.. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Hermida, Dario. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Pedersen, Anna-Kathrine. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Segura-Bayona, Sandra. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: López-Méndez, Blanca. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Redondo, Pilar. Centro Nacional de Investigaciones Oncológicas; España
Fil: Rüther, Patrick. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Pozdnyakova, Irina. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Garrote López, Ana Marcela. Centro Nacional de Investigaciones Oncológicas; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones En Biodiversidad y Biotecnología. Grupo de Investigación en Química Analítica y Modelado Molecular; Argentina
Fil: Muñoz, Inés G.. Centro Nacional de Investigaciones Oncológicas; España
Fil: Villamor-Payà, Marina. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Jauset, Cristina. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Olsen, Jesper V.. Faculty Of Health And Medical Sciences; Dinamarca
Fil: Stracker, Travis H.. Irb Barcelona - Institute For Research In Biomedicine; España
Fil: Montoya, Guillermo. Faculty Of Health And Medical Sciences; Dinamarca
description Tousled-like kinases (TLKs) are required for genome stability and normal development in numerous organisms and have been implicated in breast cancer and intellectual disability. In humans, the similar TLK1 and TLK2 interact with each other and TLK activity enhances ASF1 histone binding and is inhibited by the DNA damage response, although the molecular mechanisms of TLK regulation remain unclear. Here we describe the crystal structure of the TLK2 kinase domain. We show that the coiled-coil domains mediate dimerization and are essential for activation through ordered autophosphorylation that promotes higher order oligomers that locally increase TLK2 activity. We show that TLK2 mutations involved in intellectual disability impair kinase activity, and the docking of several small-molecule inhibitors of TLK activity suggest that the crystal structure will be useful for guiding the rationale design of new inhibition strategies. Together our results provide insights into the structure and molecular regulation of the TLKs.
publishDate 2018
dc.date.none.fl_str_mv 2018-12
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/11336/210686
Mortuza, Gulnahar B.; Hermida, Dario; Pedersen, Anna-Kathrine; Segura-Bayona, Sandra; López-Méndez, Blanca; et al.; Molecular basis of Tousled-Like Kinase 2 activation; Nature Publishing Group; Nature Communications; 9; 1; 12-2018
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/210686
identifier_str_mv Mortuza, Gulnahar B.; Hermida, Dario; Pedersen, Anna-Kathrine; Segura-Bayona, Sandra; López-Méndez, Blanca; et al.; Molecular basis of Tousled-Like Kinase 2 activation; Nature Publishing Group; Nature Communications; 9; 1; 12-2018
2041-1723
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-018-04941-y
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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
_version_ 1844613418612424704
score 13.070432

Publicaciones similares