Binding of the cSH3 domain of Grb2 adaptor to two distinct RXXK motifs within Gab1 docker employs differential mechanisms

Caleb B. McDonald, Kenneth L. Seldeen, Brian J. Deegan, Vikas Bhat, Amjad Farooq

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

A ubiquitous component of cellular signaling machinery, Gab1 docker plays a pivotal role in routing extracellular information in the form of growth factors and cytokines to downstream targets such as transcription factors within the nucleus. Here, using isothermal titration calorimetry (ITC) in combination with macromolecular modeling (MM), we show that although Gab1 contains four distinct RXXK motifs, designated G1, G2, G3, and G4, only G1 and G2 motifs bind to the cSH3 domain of Grb2 adaptor and do so with distinct mechanisms. Thus, while the G1 motif strictly requires the PPRPPKP consensus sequence for high-affinity binding to the cSH3 domain, the G2 motif displays preference for the PXVXRXLKPXR consensus. Such sequential differences in the binding of G1 and G2 motifs arise from their ability to adopt distinct polyproline type II (PPII)- and 3 10-helical conformations upon binding to the cSH3 domain, respectively. Collectively, our study provides detailed biophysical insights into a key protein-protein interaction involved in a diverse array of signaling cascades central to health and disease.

Original languageEnglish (US)
Pages (from-to)585-596
Number of pages12
JournalJournal of Molecular Recognition
Volume24
Issue number4
DOIs
StatePublished - Jul 2011

Keywords

  • Gab1 docker
  • Grb2 adaptor
  • isothermal titration calorimetry
  • macromolecular modeling
  • SH3-ligand thermodynamics

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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