Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, t...

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Autores principales:	Louise Pinet, Nadine Assrir, Carine van Heijenoort
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	intrinsic disorder signal transduction receptor tyrosine kinases ErbB EGFR HER Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/edb38888156840d1ba6101ba4af8ea9f
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spelling	oai:doaj.org-article:edb38888156840d1ba6101ba4af8ea9f2021-11-25T16:53:51ZExpanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs10.3390/biom111116902218-273Xhttps://doaj.org/article/edb38888156840d1ba6101ba4af8ea9f2021-11-01T00:00:00Zhttps://www.mdpi.com/2218-273X/11/11/1690https://doaj.org/toc/2218-273XErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.Louise PinetNadine AssrirCarine van HeijenoortMDPI AGarticleintrinsic disordersignal transductionreceptor tyrosine kinasesErbBEGFRHERMicrobiologyQR1-502ENBiomolecules, Vol 11, Iss 1690, p 1690 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	intrinsic disorder signal transduction receptor tyrosine kinases ErbB EGFR HER Microbiology QR1-502
spellingShingle	intrinsic disorder signal transduction receptor tyrosine kinases ErbB EGFR HER Microbiology QR1-502 Louise Pinet Nadine Assrir Carine van Heijenoort Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
description	ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.
format	article
author	Louise Pinet Nadine Assrir Carine van Heijenoort
author_facet	Louise Pinet Nadine Assrir Carine van Heijenoort
author_sort	Louise Pinet
title	Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
title_short	Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
title_full	Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
title_fullStr	Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
title_full_unstemmed	Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
title_sort	expanding the disorder-function paradigm in the c-terminal tails of erbbs
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/edb38888156840d1ba6101ba4af8ea9f
work_keys_str_mv	AT louisepinet expandingthedisorderfunctionparadigminthecterminaltailsoferbbs AT nadineassrir expandingthedisorderfunctionparadigminthecterminaltailsoferbbs AT carinevanheijenoort expandingthedisorderfunctionparadigminthecterminaltailsoferbbs
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Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

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