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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/49381
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:37:03Zoai: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:34982025-09-29 10:37:03.872CONICET 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 |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) |
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CONICET Digital (CONICET) |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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13.070432 |