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Tytuł:
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The intramolecular allostery of GRB2 governing its interaction with SOS1 is modulated by phosphotyrosine ligands.
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Autorzy:
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Kazemein Jasemi NS; Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany.
Herrmann C; Department of Physical Chemistry I, Ruhr University Bochum, Bochum, Germany.
Magdalena Estirado E; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, PO Box 513, 5600MB Eindhoven, The Netherlands.
Gremer L; Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, 52425 Jülich, Germany.
Willbold D; Institute of Physical Biology, Heinrich Heine University Düsseldorf, 40204 Düsseldorf, Germany.; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich, 52425 Jülich, Germany.
Brunsveld L; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, PO Box 513, 5600MB Eindhoven, The Netherlands.
Dvorsky R; Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany.
Ahmadian MR; Institute of Biochemistry and Molecular Biology II, Medical Faculty of the Heinrich-Heine University, 40225 Düsseldorf, Germany.
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Źródło:
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The Biochemical journal [Biochem J] 2021 Jul 30; Vol. 478 (14), pp. 2793-2809.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
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MeSH Terms:
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Protein Domains*
src Homology Domains*
GRB2 Adaptor Protein/*chemistry
Phosphotyrosine/*chemistry
SOS1 Protein/*chemistry
Amino Acid Sequence ; Binding Sites/genetics ; GRB2 Adaptor Protein/genetics ; GRB2 Adaptor Protein/metabolism ; Humans ; Kinetics ; Ligands ; Models, Molecular ; Phosphotyrosine/metabolism ; Protein Binding ; SOS1 Protein/genetics ; SOS1 Protein/metabolism
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Contributed Indexing:
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Keywords: GRB2; RAS GTPase; SH2; SH3; SOS1; proline-rich motif
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Substance Nomenclature:
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0 (GRB2 Adaptor Protein)
0 (GRB2 protein, human)
0 (Ligands)
0 (SOS1 Protein)
21820-51-9 (Phosphotyrosine)
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Entry Date(s):
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Date Created: 20210707 Date Completed: 20211129 Latest Revision: 20211129
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Update Code:
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20240105
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DOI:
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10.1042/BCJ20210105
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PMID:
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34232285
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Growth factor receptor-bound protein 2 (GRB2) is a trivalent adaptor protein and a key element in signal transduction. It interacts via its flanking nSH3 and cSH3 domains with the proline-rich domain (PRD) of the RAS activator SOS1 and via its central SH2 domain with phosphorylated tyrosine residues of receptor tyrosine kinases (RTKs; e.g. HER2). The elucidation of structural organization and mechanistic insights into GRB2 interactions, however, remain challenging due to their inherent flexibility. This study represents an important advance in our mechanistic understanding of how GRB2 links RTKs to SOS1. Accordingly, it can be proposed that (1) HER2 pYP-bound SH2 potentiates GRB2 SH3 domain interactions with SOS1 (an allosteric mechanism); (2) the SH2 domain blocks cSH3, enabling nSH3 to bind SOS1 first before cSH3 follows (an avidity-based mechanism); and (3) the allosteric behavior of cSH3 to other domains appears to be unidirectional, although there is an allosteric effect between the SH2 and SH3 domains.
(© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
