Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Allostery has evolved as a form of local communication between interacting protein partners allowing them to quickly sense changes in their immediate vicinity in response to external cues. Herein, using isothermal titration calorimetry (ITC) in conjunction with circular dichroism (CD) and macromolecular modeling (MM), we show that the binding of Grb2 adaptor-a key signaling molecule involved in the activation of Ras GTPase-to its downstream partners Sos1 guanine nucleotide exchange factor and Gab1 docker is under tight allosteric regulation. Specifically, our findings reveal that the binding of one molecule of Sos1 to the nSH3 domain allosterically induces a conformational change within Grb2 such that the loading of a second molecule of Sos1 onto the cSH3 domain is blocked and, in so doing, allows Gab1 access to the cSH3 domain in an exclusively non-competitive manner to generate the Sos1-Grb2-Gab1 ternary signaling complex.

Original languageEnglish
Pages (from-to)216-225
Number of pages10
JournalArchives of Biochemistry and Biophysics
Volume494
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Allosteric Regulation
Guanine Nucleotide Exchange Factors
ras Proteins
Calorimetry
Circular Dichroism
Cues
Communication
Molecules
Proteins
Titration
Chemical activation

Keywords

  • Allosteric regulation
  • Circular dichroism
  • Isothermal titration calorimetry
  • Macromolecular modeling
  • SH3-ligand thermodynamics
  • Sos1-Grb2-Gab1 ternary signaling complex

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control. / McDonald, Caleb B.; Seldeen, Kenneth L.; Deegan, Brian J.; Bhat, Vikas; Farooq, Amjad.

In: Archives of Biochemistry and Biophysics, Vol. 494, No. 2, 01.02.2010, p. 216-225.

Research output: Contribution to journalArticle

McDonald, Caleb B. ; Seldeen, Kenneth L. ; Deegan, Brian J. ; Bhat, Vikas ; Farooq, Amjad. / Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control. In: Archives of Biochemistry and Biophysics. 2010 ; Vol. 494, No. 2. pp. 216-225.
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