Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.[5][6]
The protein encoded by this gene binds receptors such as the epidermal growth factor receptor and contains one SH2 domain and two SH3 domains. Its two SH3 domains direct complex formation with proline-rich regions of other proteins, and its SH2 domain binds tyrosine phosphorylated sequences. This gene is similar to the sem-5 gene of Caenorhabditis elegans, which is involved in the signal transduction pathway. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene.[7]
Grb2 is widely expressed and is essential for multiple cellular functions. Inhibition of Grb2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. It is thus not surprising that targeted gene disruption of Grb2 in mice is lethal at an early embryonic stage. Grb2 is best known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of Ras and its downstream kinases, ERK1,2. Grb2 is composed of an SH2 domain flanked on each side by an SH3 domain. Grb2 has two closely related proteins with similar domain organizations, Gads and Grap. Gads and Grap are expressed specifically in hematopoietic cells and function in the coordination of tyrosine kinase mediated signal transduction.
The SH2 domain of Grb2 binds to phosphorylated tyrosine-containing peptides on receptors or scaffold proteins with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine (see [1]).
The N-terminal SH3 domain binds to proline-rich peptides and can bind to the Ras-guanine exchange factor SOS.
The C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1.[8]
Grb2 has been shown to interact with:
PDB gallery
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1aze: NMR STRUCTURE OF THE COMPLEX BETWEEN THE C32S-Y7V MUTANT OF THE NSH3 DOMAIN OF GRB2 WITH A PEPTIDE FROM SOS, 10 STRUCTURES
1bm2: GRB2-SH2 DOMAIN IN COMPLEX WITH CYCLO-[N-ALPHA-ACETYL-L-THI ALYSYL-O-PHOSPHOTYROSYL-VALYL-ASPARAGYL-VALYL-PROLYL] (PKF273-791)
1bmb: GRB2-SH2 DOMAIN IN COMPLEX WITH KPFY*VNVEF (PKF270-974)
1cj1: GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN (HUMAN) COMPLEXED WITH A PHOSPHOTYROSYL DERIVATIVE
1fhs: THE THREE-DIMENSIONAL SOLUTION STRUCTURE OF THE SRC HOMOLOGY DOMAIN-2 OF THE GROWTH FACTOR RECEPTOR BOUND PROTEIN-2, NMR, 18 STRUCTURES
1fyr: DIMER FORMATION THROUGH DOMAIN SWAPPING IN THE CRYSTAL STRUCTURE OF THE GRB2-SH2 AC-PYVNV COMPLEX
1gbq: SOLUTION NMR STRUCTURE OF THE GRB2 N-TERMINAL SH3 DOMAIN COMPLEXED WITH A TEN-RESIDUE PEPTIDE DERIVED FROM SOS DIRECT REFINEMENT AGAINST NOES, J-COUPLINGS, AND 1H AND 13C CHEMICAL SHIFTS, MINIMIZED AVERAGE STRUCTURE
1gbr: ORIENTATION OF PEPTIDE FRAGMENTS FROM SOS PROTEINS BOUND TO THE N-TERMINAL SH3 DOMAIN OF GRB2 DETERMINED BY NMR SPECTROSCOPY
1gcq: CRYSTAL STRUCTURE OF VAV AND GRB2 SH3 DOMAINS
1gfc: SOLUTION STRUCTURE AND LIGAND-BINDING SITE OF THE C-TERMINAL SH3 DOMAIN OF GRB2
1gfd: SOLUTION STRUCTURE AND LIGAND-BINDING SITE OF THE C-TERMINAL SH3 DOMAIN OF GRB2
1ghu: NMR solution structure of growth factor receptor-bound protein 2 (GRB2) SH2 domain, 24 structures
1gri: GRB2
1io6: GROWTH FACTOR RECEPTOR-BOUND PROTEIN 2 (GRB2) C-TERMINAL SH3 DOMAIN COMPLEXED WITH A LIGAND PEPTIDE (NMR, MINIMIZED MEAN STRUCTURE)
1jyq: Xray Structure of Grb2 SH2 Domain Complexed with a Highly Affine Phospho Peptide
1jyr: Xray Structure of Grb2 SH2 Domain Complexed with a Phosphorylated Peptide
1jyu: Xray Structure of Grb2 SH2 Domain
1qg1: GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN COMPLEXED WITH AN SHC-DERIVED PEPTIDE
1tze: SIGNAL TRANSDUCTION ADAPTOR GROWTH FACTOR, GRB2 SH2 DOMAIN COMPLEXED WITH PHOSPHOTYROSYL HEPTAPEPTIDE LYS-PRO-PHE-PTYR-VAL-ASN-VAL-NH2 (KFPPYVNC-NH2)
1x0n: NMR structure of growth factor receptor binding protein SH2 domain complexed with the inhibitor
1zfp: GROWTH FACTOR RECEPTOR BINDING PROTEIN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PENTAPEPTIDE
2aoa: Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
2aob: Crystal structures of a high-affinity macrocyclic peptide mimetic in complex with the Grb2 SH2 domain
2gbq: SOLUTION NMR STRUCTURE OF THE GRB2 N-TERMINAL SH3 DOMAIN COMPLEXED WITH A TEN-RESIDUE PEPTIDE DERIVED FROM SOS DIRECT REFINEMENT AGAINST NOES, J-COUPLINGS, AND 1H AND 13C CHEMICAL SHIFTS, 15 STRUCTURES
2h46: Native domain-swapped dimer crystal structure of the Grb2 SH2 domain
2h5k: Crystal Structure of Complex Between the Domain-Swapped Dimeric Grb2 SH2 Domain and Shc-Derived Ligand, Ac-NH-pTyr-Val-Asn-NH2
2huw: X-ray crystal structure of the Grb2 SH2 domain complexed to a constrained and cyclopropane-derived ligand
2huy:
3gbq: SOLUTION NMR STRUCTURE OF THE GRB2 N-TERMINAL SH3 DOMAIN COMPLEXED WITH A TEN-RESIDUE PEPTIDE DERIVED FROM SOS DIRECT REFINEMENT AGAINST NOES, J-COUPLINGS, AND 1H AND 13C CHEMICAL SHIFTS, MINIMIZED AVERAGE STRUCTURE
4gbq: SOLUTION NMR STRUCTURE OF THE GRB2 N-TERMINAL SH3 DOMAIN COMPLEXED WITH A TEN-RESIDUE PEPTIDE DERIVED FROM SOS DIRECT REFINEMENT AGAINST NOES, J-COUPLINGS, AND 1H AND 13C CHEMICAL SHIFTS, 15 STRUCTURES
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