The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.

Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2...

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Autores principales:	Nicole Dölker, Maria W Górna, Ludovico Sutto, Antonio S Torralba, Giulio Superti-Furga, Francesco L Gervasio
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/70490370a7bd4113b7a2ca9f1d6a10ff
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spelling	oai:doaj.org-article:70490370a7bd4113b7a2ca9f1d6a10ff2021-11-25T05:40:41ZThe SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.1553-734X1553-735810.1371/journal.pcbi.1003863https://doaj.org/article/70490370a7bd4113b7a2ca9f1d6a10ff2014-10-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1003863https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.Nicole DölkerMaria W GórnaLudovico SuttoAntonio S TorralbaGiulio Superti-FurgaFrancesco L GervasioPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 10, p e1003863 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Nicole Dölker Maria W Górna Ludovico Sutto Antonio S Torralba Giulio Superti-Furga Francesco L Gervasio The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
description	Regulation of the c-Abl (ABL1) tyrosine kinase is important because of its role in cellular signaling, and its relevance in the leukemiogenic counterpart (BCR-ABL). Both auto-inhibition and full activation of c-Abl are regulated by the interaction of the catalytic domain with the Src Homology 2 (SH2) domain. The mechanism by which this interaction enhances catalysis is not known. We combined computational simulations with mutagenesis and functional analysis to find that the SH2 domain conveys both local and global effects on the dynamics of the catalytic domain. Locally, it regulates the flexibility of the αC helix in a fashion reminiscent of cyclins in cyclin-dependent kinases, reorienting catalytically important motifs. At a more global level, SH2 binding redirects the hinge motion of the N and C lobes and changes the conformational equilibrium of the activation loop. The complex network of subtle structural shifts that link the SH2 domain with the activation loop and the active site may be partially conserved with other SH2-domain containing kinases and therefore offer additional parameters for the design of conformation-specific inhibitors.
format	article
author	Nicole Dölker Maria W Górna Ludovico Sutto Antonio S Torralba Giulio Superti-Furga Francesco L Gervasio
author_facet	Nicole Dölker Maria W Górna Ludovico Sutto Antonio S Torralba Giulio Superti-Furga Francesco L Gervasio
author_sort	Nicole Dölker
title	The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
title_short	The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
title_full	The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
title_fullStr	The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
title_full_unstemmed	The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
title_sort	sh2 domain regulates c-abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/70490370a7bd4113b7a2ca9f1d6a10ff
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The SH2 domain regulates c-Abl kinase activation by a cyclin-like mechanism and remodulation of the hinge motion.

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