Unmasking Determinants of Specificity in the Human Kinome

Autores
Creixell, Pau; Palmeri, Antonio; Miller, Chad J.; Lou, Hua Jane; Santini, Cristina C.; Nielsen, Morten; Turk, Benjamin E.; Linding, Rune
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).
Fil: Creixell, Pau. Technical University of Denmark; Dinamarca
Fil: Palmeri, Antonio. Universita Tor Vergata; Italia
Fil: Miller, Chad J.. University of Yale; Estados Unidos
Fil: Lou, Hua Jane. University of Yale; Estados Unidos
Fil: Santini, Cristina C.. Universidad de Copenhagen; Dinamarca. Technical University of Denmark; Dinamarca
Fil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Turk, Benjamin E.. University of Yale; Estados Unidos
Fil: Linding, Rune. Technical University of Denmark; Dinamarca. Universidad de Copenhagen; Dinamarca
Materia
Protein kinases
Determinants of specificity
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:11336/49381
Acceder
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network_acronym_str CONICETDig
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network_name_str CONICET Digital (CONICET)
spelling Unmasking Determinants of Specificity in the Human KinomeCreixell, PauPalmeri, AntonioMiller, Chad J.Lou, Hua JaneSantini, Cristina C.Nielsen, MortenTurk, Benjamin E.Linding, RuneProtein kinasesDeterminants of specificityhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).Fil: Creixell, Pau. Technical University of Denmark; DinamarcaFil: Palmeri, Antonio. Universita Tor Vergata; ItaliaFil: Miller, Chad J.. University of Yale; Estados UnidosFil: Lou, Hua Jane. University of Yale; Estados UnidosFil: Santini, Cristina C.. Universidad de Copenhagen; Dinamarca. Technical University of Denmark; DinamarcaFil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Turk, Benjamin E.. University of Yale; Estados UnidosFil: Linding, Rune. Technical University of Denmark; Dinamarca. Universidad de Copenhagen; DinamarcaCell Press2015-09info: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/11336/49381Creixell, Pau; Palmeri, Antonio; Miller, Chad J.; Lou, Hua Jane; Santini, Cristina C.; et al.; Unmasking Determinants of Specificity in the Human Kinome; Cell Press; Cell; 163; 1; 9-2015; 187-2010092-8674CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.cell.2015.08.057info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0092867415011095info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:09:16Zoai:ri.conicet.gov.ar:11336/49381instacron: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:34982025-10-22 12:09:17.154CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Unmasking Determinants of Specificity in the Human Kinome
title Unmasking Determinants of Specificity in the Human Kinome
spellingShingle Unmasking Determinants of Specificity in the Human Kinome
Creixell, Pau
Protein kinases
Determinants of specificity
title_short Unmasking Determinants of Specificity in the Human Kinome
title_full Unmasking Determinants of Specificity in the Human Kinome
title_fullStr Unmasking Determinants of Specificity in the Human Kinome
title_full_unstemmed Unmasking Determinants of Specificity in the Human Kinome
title_sort Unmasking Determinants of Specificity in the Human Kinome
dc.creator.none.fl_str_mv Creixell, Pau
Palmeri, Antonio
Miller, Chad J.
Lou, Hua Jane
Santini, Cristina C.
Nielsen, Morten
Turk, Benjamin E.
Linding, Rune
author Creixell, Pau
author_facet Creixell, Pau
Palmeri, Antonio
Miller, Chad J.
Lou, Hua Jane
Santini, Cristina C.
Nielsen, Morten
Turk, Benjamin E.
Linding, Rune
author_role author
author2 Palmeri, Antonio
Miller, Chad J.
Lou, Hua Jane
Santini, Cristina C.
Nielsen, Morten
Turk, Benjamin E.
Linding, Rune
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Protein kinases
Determinants of specificity
topic Protein kinases
Determinants of specificity
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).
Fil: Creixell, Pau. Technical University of Denmark; Dinamarca
Fil: Palmeri, Antonio. Universita Tor Vergata; Italia
Fil: Miller, Chad J.. University of Yale; Estados Unidos
Fil: Lou, Hua Jane. University of Yale; Estados Unidos
Fil: Santini, Cristina C.. Universidad de Copenhagen; Dinamarca. Technical University of Denmark; Dinamarca
Fil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Turk, Benjamin E.. University of Yale; Estados Unidos
Fil: Linding, Rune. Technical University of Denmark; Dinamarca. Universidad de Copenhagen; Dinamarca
description Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).
publishDate 2015
dc.date.none.fl_str_mv 2015-09
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/11336/49381
Creixell, Pau; Palmeri, Antonio; Miller, Chad J.; Lou, Hua Jane; Santini, Cristina C.; et al.; Unmasking Determinants of Specificity in the Human Kinome; Cell Press; Cell; 163; 1; 9-2015; 187-201
0092-8674
CONICET Digital
CONICET
url http://hdl.handle.net/11336/49381
identifier_str_mv Creixell, Pau; Palmeri, Antonio; Miller, Chad J.; Lou, Hua Jane; Santini, Cristina C.; et al.; Unmasking Determinants of Specificity in the Human Kinome; Cell Press; Cell; 163; 1; 9-2015; 187-201
0092-8674
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.cell.2015.08.057
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0092867415011095
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
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 12.982451

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