Adaptor proteins are accessories to main proteins in signal transduction pathways that usually lack intrinsic enzymatic activity but instead facilitate the linking of binding partners together to enable the formation of larger signaling complexes. One widely expressed adaptor protein is the growth factor receptor-bound protein 2 (GRB2), which facilitates formation of cytoplasmic signaling complexes from a wide array of binding partners, including (among others) growth factor receptors, cytokine receptors and T cell receptor (TCR) ζ chains. As a consequence, the structure and function of GRB2 have become major areas of investigation for novel areas of interventions against various human diseases. GRB2 has been shown to exist in either a monomeric or dimeric state, where GRB2 dimers are formed by the exchange of protein segments between domains, a process termed “domain-swapping”. Prior to this work, swapping between the SH2 and SH3 domains of GRB2 has been demonstrated in the full-length structure, but SH2/SH2 domain-swapping had not. Researchers at the University of Iowa generated a model of full-length GRB2 dimer with an SH2/SH2 domain-swapped conformation, and proceeded to validate the model in solution using SEC-MALS-SAXS experiments at BioCAT. They were able to further validated their model with GRB2 mutants that favored either a monomeric or a dimeric state through mutations within the SH2 domain that either forbid or promote SH2/SH2 domain-swapping. Together with knockdown and re-expression studies, the authors showed that a novel dimeric GRB2 conformation with domain-swapping between SH2 domains and monomer/dimer transitions are critical for GRB2 to facilitate early signaling complexes in human T cells.
See: Aline Sandouk, Zhen Xu, Sankar Baruah, Mikaela Tremblay, Jesse B Hopkins, Srinivas Chakravarthy, Lokesh Gakhar, Nicholas J Schnicker, Jon C D Houtman. GRB2 dimerization mediated by SH2 domain-swapping is critical for T cell signaling and cytokine production. Sci Rep. 13, 3505 (2023). DOI: 10.1038/s41598-023-30562-7. PMCID: PMC9981690