title: Assembly of the Sos1-Grb2-Gab1 ternary signaling complex is under allosteric control.
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.
authors.affiliation: Department of Biochemistry & Molecular Biology and USylvester Braman Family Breast Cancer Institute, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Caleb B
authors.initials: CB
authors.lastname: McDonald
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Seldeen
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Deegan
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhat
authors.forename: Amjad
authors.initials: A
authors.lastname: Farooq
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D002151:Calorimetry; D002942:Circular Dichroism; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D020837:SOS1 Protein / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010446:Peptide Fragments; D020837:SOS1 Protein