Modulation of SHP-1 phosphatase activity by monovalent and bivalent SH2 phosphopeptide ligands

Kathleen Teichmann, Toni Kühl, Ina Könnig, Karin Wieligmann, Martin Zacharias, Diana Imhof

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

A sequence derived from the epithelial receptor tyrosine kinase Ros (pY2267) represents a high-affinity binding partner for protein tyrosine phosphatase SHP-1 and was recently used as lead structure to analyze the recognition requirements for the enzyme's N-SH2 domain. Here, we focused on a set of peptides comprising C-terminally extended linear and conformationally constrained side chain-bridged cyclic N-SH2 ligands based on the consensus sequence LxpYhxh(h/b)(h/b) (x = any amino acid, h = hydrophobic, and b = basic residue). Furthermore, the bivalent peptides described were designed to modulate the activity of SHP-1 through binding to both, the N-SH2 domain as well as an independent binding site on the surface of the catalytic domain (PTP domain). Consistent with previous experimental findings, surface plasmon resonance experiments revealed dissociation constants of most compounds in the low micromolar range. One peptide, EGLNpYc[KVD]MFPAPEEE - NH2, displayed favorable binding affinity, but reduced ability to stimulate SHP-1. Docking experiments revealed that the binding of this ligand occurs in binding mode I, recently described to lead to an inhibited activation of SHP-1. In summary, results presented in this study suggest that inhibitory N-SH2 ligands of SHP-1 may be obtained by designing bivalent compounds that associate with the N-SH2 domain and simultaneously occupy a specific binding site on the PTP domain.

Original languageEnglish
Pages (from-to)102-112
Number of pages11
JournalBiopolymers
Volume93
Issue number1
DOIs
StatePublished - 2010
Externally publishedYes

Keywords

  • Phosphotyrosyl peptides
  • SH2 domain ligands
  • SHP-1
  • Surface plasmon resonance
  • Tyrosine phosphatases

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