title: Allostery mediates ligand binding to Grb2 adaptor in a mutually exclusive manner.
abstract: Allostery plays a key role in dictating the stoichiometry and thermodynamics of multi-protein complexes driving a plethora of cellular processes central to health and disease. Herein, using various biophysical tools, we demonstrate that although Sos1 nucleotide exchange factor and Gab1 docking protein recognize two non-overlapping sites within the Grb2 adaptor, allostery promotes the formation of two distinct pools of Grb2-Sos1 and Grb2-Gab1 binary signaling complexes in concert in lieu of a composite Sos1-Grb2-Gab1 ternary complex. Of particular interest is the observation that the binding of Sos1 to the nSH3 domain within Grb2 sterically blocks the binding of Gab1 to the cSH3 domain and vice versa in a mutually exclusive manner. Importantly, the formation of both the Grb2-Sos1 and Grb2-Gab1 binary complexes is governed by a stoichiometry of 2:1, whereby the respective SH3 domains within Grb2 homodimer bind to Sos1 and Gab1 via multivalent interactions. Collectively, our study sheds new light on the role of allostery in mediating cellular signaling machinery.
authors: Department of Biochemistry and Molecular Biology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors: Caleb B
authors: CB
authors: McDonald
authors: Jimmy
authors: J
authors: El Hokayem
authors: Nawal
authors: N
authors: Zafar
authors: Jordan E
authors: JE
authors: Balke
authors: Vikas
authors: V
authors: Bhat
authors: David C
authors: DC
authors: Mikles
authors: Brian J
authors: BJ
authors: Deegan
authors: Kenneth L
authors: KL
authors: Seldeen
authors: Amjad
authors: A
authors: Farooq
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics; D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D001665:Binding Sites; D004926:Escherichia coli / Q000235:genetics; D051380:GRB2 Adaptor Protein / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D020837:SOS1 Protein / Q000737:chemistry* / Q000235:genetics; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C098587:GAB1 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008024:Ligands; D011994:Recombinant Proteins; D020837:SOS1 Protein