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    Characterization of the full-length human Grb7 protein and a phosphorylation representative mutant

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    Author
    Bradford, Andrew M
    Koirala, Rajan
    Park, Chad K
    Lyons, Barbara A
    Affiliation
    Univ Arizona, Dept Chem & Biochem, Analyt Biophys Core
    Issue Date
    2019-07-28
    Keywords
    Grb7 regulation
    cancer
    cell migration
    oligomerization
    tyrosine phosphorylation
    
    Metadata
    Show full item record
    Publisher
    WILEY
    Citation
    Bradford, AM, Koirala, R, Park, CK, Lyons, BA. Characterization of the full‐length human Grb7 protein and a phosphorylation representative mutant. J Mol Recognit. 2019;e2803. https://doi.org/10.1002/jmr.2803
    Journal
    JOURNAL OF MOLECULAR RECOGNITION
    Rights
    © 2019 John Wiley & Sons, Ltd.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    It is well known the dimerization state of receptor tyrosine kinases (RTKs), in conjunction with binding partners such as the growth factor receptor bound protein 7 (Grb7) protein, plays an important role in cell signaling regulation. Previously, we proposed, downstream of RTKs, that the phosphorylation state of Grb7SH2 domain tyrosine residues could control Grb7 dimerization, and dimerization may be an important regulatory step in Grb7 binding to RTKs. In this manner, additional dimerization-dependent regulation could occur downstream of the membrane-bound kinase in RTK-mediated signaling pathways. Extrapolation to the full-length (FL) Grb7 protein, and the ability to test this hypothesis further, has been hampered by the availability of large quantities of pure and stable FL protein. Here, we report the biophysical characterization of the FL Grb7 protein and also a mutant representing a tyrosine-phosphorylated Grb7 protein form. Through size exclusion chromatography and analytical ultracentrifugation, we show the phosphorylated-tyrosine-mimic Y492E-FL-Grb7 protein (Y492E-FL-Grb7) is essentially monomeric at expected physiological concentrations. It has been shown previously the wild-type FL Grb7(WT-FLGrb7) protein is dimeric with a dissociation constant (Kd) of approximately 11μM. Our studies here measure a FL protein dimerization Kd of WT-FL-Grb7 within one order of magnitude at approximately 1μM. The approximate size and shape of the WT-FL-Grb7 in comparison the tyrosine-phosphorylation mimic Y492E-FL-Grb7 protein was determined by dynamic light scattering methods. In vitro phosphorylation of the Grb7SH2 domain indicates only one of the available tyrosine residues is phosphorylated, suggesting the same phosphorylation pattern could be relevant in the FL protein. The biophysical characterization studies in total are interpreted with a view towards understanding the functionally active Grb7 protein conformation.
    Note
    12 month embargo; published online: 28 July 2019
    ISSN
    0952-3499
    PubMed ID
    31353673
    DOI
    10.1002/jmr.2803
    Version
    Final accepted manuscript
    Sponsors
    NIH [P20GM103451, SC3 GM116728]
    ae974a485f413a2113503eed53cd6c53
    10.1002/jmr.2803
    Scopus Count
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