Structure of the N-terminal SH3 domain of GRB2 complexed with a peptide from the guanine nucleotide releasing factor Sos

Terasawa, Hiroaki; Kohda, Daisuke; Hatanaka, Hideki; Tsuchiya, Shunji; Ogura, Kenji; Nagata, Koji; Ishii, Shunsuke; Mandiyan, Valsan; Ullrich, Axel; Schlessinger, Joseph; Inagaki, Fuyuhiko

doi:10.1038/nsb1294-891

Cited by 107 publications

(107 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data contradict recent reports suggesting that GRB2-SH3N mediates binding to THEMIS (5,21). Although the reason for this discrepancy is unclear, our data do agree with published reports indicating that GRB2-SH3N preferentially binds to motifs conforming to the consensus PxxPxR (15), such as the type II polyproline helix in SOS (24), and displays only negligible affinities toward RxxK motifs (12,15). This leaves open the possibility that GRB2, via SH3N, helps in bridging LAT and THEMIS to an unknown partner.…”

Section: Discussioncontrasting

confidence: 57%

GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development

Paster

Brockmeyer

et al. 2013

The Journal of Immunology

100

View full text Add to dashboard Cite

Thymocyte-expressed molecule involved in selection (THEMIS) is a recently identified regulator of thymocyte positive selection. THEMIS’s mechanism of action is unknown, and whether it has a role in TCR-proximal signaling is controversial. In this article, we show that THEMIS and the adapter molecule growth factor receptor–bound protein 2 (GRB2) associate constitutively through binding of a conserved PxRPxK motif within the proline-rich region 1 of THEMIS to the C-terminal SH3-domain of GRB2. This association is indispensable for THEMIS recruitment to the immunological synapse via the transmembrane adapter linker for activation of T cells (LAT) and for THEMIS phosphorylation by Lck and ZAP-70. Two major sites of tyrosine phosphorylation were mapped to a YY-motif close to proline-rich region 1. The YY-motif was crucial for GRB2 binding, suggesting that this region of THEMIS might control local phosphorylation-dependent conformational changes important for THEMIS function. Finally, THEMIS binding to GRB2 was required for thymocyte development. Our data firmly assign THEMIS to the TCR-proximal signaling cascade as a participant in the LAT signalosome and suggest that the THEMIS–GRB2 complex might be involved in shaping the nature of Ras signaling, thereby governing thymic selection.

show abstract

Section: Discussioncontrasting

confidence: 57%

GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development

Paster

Brockmeyer

et al. 2013

The Journal of Immunology

100

View full text Add to dashboard Cite

show abstract

“…We have observed that the presence of a second arginine at the C-terminal end of the proline-rich peptide (PVPPPVPPRR) increases the affinity for Grb2 and gives a two times higher tryptophan fluorescence signal, suggesting that the arginines come close to the conserved tryptophan of the SH3 domain [4]. However, the NMR structure of the isolated Grb2 N-SH3 shows that the second arginine does not bind to the SH3 [34,35], it seems to help this region of the peptide to adopt a helical conformation that places the first arginine in an appropriate position (Fig. 3).…”

Section: Properties Of Grb2 Sh3 Domainsmentioning

confidence: 92%

“…The acidic cluster around positions 30, 31, 33 of the N-ter SH3 is the most mobile loop of the structure. Surprisingly, it was found that the SH3 domains of Grb2 bind proline rich peptides in the opposite orientation than Abl, PI3Kinase and Fyn [34][35][36]. This is made possible by the pseudo-symetry of the polyproline II helix.…”

Section: Properties Of Grb2 Sh3 Domainsmentioning

confidence: 99%

See 1 more Smart Citation

The Grb2 adaptor

et al. 1995

View full text Add to dashboard Cite

Grb2 is an 'adaptor' protein made of one SH2 and two SH3 domains. The SH3 domains bind to prolinerich motifs in the C-terminal part of the ras exchange factor Sos. Binding of the Grb2 SH2 domain to phosphotyrosine motifs on receptors, or other adaptor proteins such as Shc, recruits this Grb21Sos complex at the plasma membrane where Sos stimulates nucleotide exchange on ras, then ras activates raf and leads to MAP kinase activation. The structure of Grb2, the precise motifs recognised by its SH2 and SH3 domains, the way Grb2 performs its function, a possible regulation of its association with Sos, and its ability to complex with other proteins in vivo, are discussed.

show abstract

“…Hence, molecules whose shapes complement the protein interaction clefts of the ligand surfaces are likely to block receptor binding (4). Previously, several linear peptides with extended polyproline type II (PP II ) 1 conformation have been shown to block ligand-acceptor complexes involved in molecular recognition (5)(6)(7). Acceptors are typically large proteins with measurable affinity for specific ligands; the latter can be presented as a small peptide sequence within an exposed loop on the surface of a large protein.…”

mentioning

confidence: 99%

CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation

Srinivasan

Eri

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The critical role played by the CD28/CD152-CD80/ CD86 costimulatory molecules in mediating T cell activation and suppression provides attractive targets for therapeutic strategies. CD28 and CD152 share a conserved polyproline motif in the ligand-binding region. Similar proline-rich regions in globular domains preferentially adopt a polyproline type II (PP II ) helical conformation and are involved in transient protein-protein interactions. Interestingly, in the human CD80-CD152 complex, Pro 102 of CD152 restricts the preceding proline to PP II helix in the binding orientation in relation to the shallow binding pocket of CD80. Peptide agents derived from binding sites of receptors that mimic the bioactive conformation have been shown to block receptor-ligand interactions. Contact preferences of the interface amino acids at the protein-protein interaction sites and the propensity of each residue to form PP II helix were integrated in the design of novel peptide agents referred to as CD80 competitive antagonist peptides. Structural and functional studies suggest potential therapeutic value for select CD80 competitive antagonist peptides.The interaction between cell surface costimulatory molecules on antigen-presenting cells and the T cells is critical in modulating cell-cell communication (1). Two structurally and functionally well characterized T cell surface costimulatory molecules are CD28 and the CTLA4 (cytotoxic T lymphocyteassociated antigen)/CD152, both of which bind the same ligands, CD80 (B7-1) and CD86 (B7-2), on the antigen-presenting cells. Whereas signaling via CD28 mediates T cell activation, ligation of CD152 down-regulates T cell proliferation and function (2). Thus, CD80/CD86-CD28/CD152 costimulatory molecules are potential therapeutic targets for modulating T cell responses.Analyses of multiple receptor-ligand interactions suggest that in exposed domains involved in protein-protein interactions that mediate cell signaling, the intermolecular interfaces often present extended shallow clefts on ligand surfaces (3). Hence, molecules whose shapes complement the protein interaction clefts of the ligand surfaces are likely to block receptor binding (4). Previously, several linear peptides with extended polyproline type II (PP II ) 1 conformation have been shown to block ligand-acceptor complexes involved in molecular recognition (5-7). Acceptors are typically large proteins with measurable affinity for specific ligands; the latter can be presented as a small peptide sequence within an exposed loop on the surface of a large protein. Structurally, ligands may exist in extended PP II helical conformation, allowing the backbone atoms of the peptide to form hydrogen bonds with protein acceptor at the interface of the protein-peptide complex (8, 9). Examples of complexes where the ligand is in PP II conformation include the EFPPPPT peptide, which interacts with the VASP (vasodilator-stimulated phosphoprotein) EVH1 (Ena/VASP homology) domain (Protein Data Bank code 1QC6), and the SOS (Son of Sevenless) peptide...

show abstract

Structure of the N-terminal SH3 domain of GRB2 complexed with a peptide from the guanine nucleotide releasing factor Sos

Cited by 107 publications

References 38 publications

GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development

GRB2-Mediated Recruitment of THEMIS to LAT Is Essential for Thymocyte Development

The Grb2 adaptor

CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation

Contact Info

Product

Resources

About