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dc.contributor.authorMarasco, Michelangelo
dc.contributor.authorKirkpatrick, John
dc.contributor.authorNanna, Vittoria
dc.contributor.authorSikorska, Justyna
dc.contributor.authorCarlomagno, Teresa
dc.date.accessioned2021-09-13T12:16:40Z
dc.date.available2021-09-13T12:16:40Z
dc.date.issued2021-04-20
dc.identifier.citationComput Struct Biotechnol J. 2021 Apr 20;19:2398-2415. doi: 10.1016/j.csbj.2021.04.040.en_US
dc.identifier.issn2001-0370
dc.identifier.pmid34025932
dc.identifier.doi10.1016/j.csbj.2021.04.040
dc.identifier.urihttp://hdl.handle.net/10033/623025
dc.description.abstractSHP2 is a ubiquitous protein tyrosine phosphatase, whose activity is regulated by phosphotyrosine (pY)-containing peptides generated in response to extracellular stimuli. Its crystal structure reveals a closed, auto-inhibited conformation in which the N-terminal Src homology 2 (N-SH2) domain occludes the catalytic site of the phosphatase (PTP) domain. High-affinity mono-phosphorylated peptides promote catalytic activity by binding to N-SH2 and disrupting the interaction with the PTP. The mechanism behind this process is not entirely clear, especially because N-SH2 is incapable of accommodating complete peptide binding when SHP2 is in the auto-inhibited state. Here, we show that pY performs an essential role in this process; in addition to its contribution to overall peptide-binding energy, pY-recognition leads to enhanced dynamics of the N-SH2 EF and BG loops via an allosteric communication network, which destabilizes the N-SH2–PTP interaction surface and simultaneously generates a fully accessible binding pocket for the C-terminal half of the phosphopeptide. Subsequently, full binding of the phosphopeptide is associated with the stabilization of activated SHP2. We demonstrate that this allosteric network exists only in N-SH2, which is directly involved in the regulation of SHP2 activity, while the C-terminal SH2 domain (C-SH2) functions primarily to recruit high-affinity bidentate phosphopeptides.en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAllosteric couplingen_US
dc.subjectMolecular dynamicsen_US
dc.subjectNMR spectroscopyen_US
dc.subjectPD-1en_US
dc.subjectSHP2en_US
dc.titlePhosphotyrosine couples peptide binding and SHP2 activation via a dynamic allosteric network.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalComputational and structural biotechnology journalen_US
dc.source.volume19
dc.source.beginpage2398
dc.source.endpage2415
refterms.dateFOA2021-09-13T12:16:41Z
dc.source.journaltitleComputational and structural biotechnology journal
dc.source.countryNetherlands


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International