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Backbone nuclear relaxation characteristics and calorimetric investigation of the human Grb7-SH2/erbB2 peptide complex

¹ Department of Biochemistry, College of Medicine, University of Vermont, Burlington, Vermont 05405, USA
² Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, USA
³ Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003-8001, USA

(RECEIVED September 8, 2004; FINAL REVISION February 2, 2005; ACCEPTED March 9, 2005)

Grb7 is a member of the Grb7 family of proteins, which also includes Grb10 and Grb14. All three proteins have been found to be overexpressed in certain cancers and cancer cell lines. In particular, Grb7 (along with the receptor tyrosine kinase erbB2) is overexpressed in 20%–30% of breast cancers. Grb7 binds to erbB2 and may be involved in cell signaling pathways that promote the formation of metastases and inflammatory responses. In a prior study, we reported the solution structure of the Grb7-SH2/erbB2 peptide complex. In this study, T₁, T₂, and steady-state NOE measurements were performed on the Grb7-SH2 domain, and the backbone relaxation behavior of the domain is discussed with respect to the potential function of an insert region present in all three members of this protein family. Isothermal titration calorimetry (ITC) studies were completed measuring the thermodynamic parameters of the binding of a 10-residue phosphorylated peptide representative of erbB2 to the SH2 domain. These measurements are compared to calorimetric studies performed on other SH2 domain/phosphorylated peptide complexes available in the literature.

Abbreviations: BPS, between Plekstrin and Src • EGFR, epidermal growth factor receptor • erbB2 (aka HER2, EGFR2), erythroblastosis B • FGFR, fibroblast growth factor receptor • Grb, growth factor receptor bound • HSQC, heteronuclear single-quantum coherence • J(), spectral density function • IR, insulin receptor • ITC, isothermal titration calorimetry • NMR, nuclear magnetic resonance • NOE, nuclear Overhauser effect • NOESY, NOE spectroscopy • PDGFR, platelet derived growth factor receptor • T₁, longitudinal relaxation time (aka spin-lattice) • T₂, transverse relaxation time (aka spin–spin) • _m, molecular correlation time • _e, effective correlation time • RMSD, root-mean-square deviation • RTK, receptor tyrosine kinase • S², order parameter • SH2, Src homology 2.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041102305.

Reprint requests to: Barbara A. Lyons, Department of Chemistry and Biochemistry, MSC 3C, P.O. Box 30001, Las Cruces, NM 88003- 8001, USA; e-mail: blyons{at}nmsu.edu; fax: (505) 646-2649.

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