Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state

The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditio...

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Autores principales:	Paolo Calligari, Valerio Santucci, Lorenzo Stella, Gianfranco Bocchinfuso
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	SHP2 regulatory mechanism Replica exchange molecular dynamics simulations Inter-domain dynamics Protein flexibility Biotechnology TP248.13-248.65
Acceso en línea:	https://doaj.org/article/8c59188819124d0bb9e7f12d34ff62ec
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spelling	oai:doaj.org-article:8c59188819124d0bb9e7f12d34ff62ec2021-11-26T04:26:44ZDiscriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state2001-037010.1016/j.csbj.2021.10.041https://doaj.org/article/8c59188819124d0bb9e7f12d34ff62ec2021-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2001037021004633https://doaj.org/toc/2001-0370The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged.Paolo CalligariValerio SantucciLorenzo StellaGianfranco BocchinfusoElsevierarticleSHP2 regulatory mechanismReplica exchange molecular dynamics simulationsInter-domain dynamicsProtein flexibilityBiotechnologyTP248.13-248.65ENComputational and Structural Biotechnology Journal, Vol 19, Iss , Pp 6125-6139 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	SHP2 regulatory mechanism Replica exchange molecular dynamics simulations Inter-domain dynamics Protein flexibility Biotechnology TP248.13-248.65
spellingShingle	SHP2 regulatory mechanism Replica exchange molecular dynamics simulations Inter-domain dynamics Protein flexibility Biotechnology TP248.13-248.65 Paolo Calligari Valerio Santucci Lorenzo Stella Gianfranco Bocchinfuso Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
description	The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged.
format	article
author	Paolo Calligari Valerio Santucci Lorenzo Stella Gianfranco Bocchinfuso
author_facet	Paolo Calligari Valerio Santucci Lorenzo Stella Gianfranco Bocchinfuso
author_sort	Paolo Calligari
title	Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
title_short	Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
title_full	Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
title_fullStr	Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
title_full_unstemmed	Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
title_sort	discriminating between competing models for the allosteric regulation of oncogenic phosphatase shp2 by characterizing its active state
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8c59188819124d0bb9e7f12d34ff62ec
work_keys_str_mv	AT paolocalligari discriminatingbetweencompetingmodelsfortheallostericregulationofoncogenicphosphataseshp2bycharacterizingitsactivestate AT valeriosantucci discriminatingbetweencompetingmodelsfortheallostericregulationofoncogenicphosphataseshp2bycharacterizingitsactivestate AT lorenzostella discriminatingbetweencompetingmodelsfortheallostericregulationofoncogenicphosphataseshp2bycharacterizingitsactivestate AT gianfrancobocchinfuso discriminatingbetweencompetingmodelsfortheallostericregulationofoncogenicphosphataseshp2bycharacterizingitsactivestate
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Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state

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