Structural insights into the tyrosine phosphorylation–mediated inhibition of SH3 domain–ligand interactions

Merő, Balázs; Radnai, László; Gógl, Gergő; Tőke, Orsolya; Leveles, Ibolya; Koprivanacz, Kitti; Szeder, Bálint; Dülk, Metta; Kudlik, Gyöngyi; Vas, Virag; Cserkaszky, Anna; Sipeki, Szabolcs; Nyitray, László; Vértessy, Beáta G.; Buday, László

doi:10.1074/jbc.ra118.004732

Cited by 16 publications

(12 citation statements)

References 59 publications

(63 reference statements)

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“…Moreover, our study may provide some insight into the widespread but poorly understood phenomenon of SH3 domain tyrosine phosphorylation [77]. A recently published bioinformatic survey revealed that of 273 human SH3 domains, 94 are phosphorylated on tyrosine, and 20 of those are phosphorylated at the M2 position, which is the location of Gads Y45 [78]. Yet, with the possible exception of Src p-Y133 [79] and Caskin 1 p-Y336 [80], the functional significance of SH3 domain tyrosine phosphorylation at the M2 position is, to the best of our knowledge, unknown.…”

Section: The Itk-targeted Sites On Slp-76 and Gads Are Selectively Rementioning

confidence: 80%

Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Hallumi

Shalah

Lo³

et al. 2020

Preprint

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The costimulatory receptor, CD28, synergizes with the T cell antigen receptor (TCR) to promote IL-2 production, cell survival and proliferation. Despite their profound synergy, the obligatory interdependence of the signaling pathways initiated by these two receptors is not well understood. Upon TCR stimulation, Gads, a Grb2-family adaptor, bridges the interaction of two additional adaptors, LAT and SLP-76, to form a TCR-induced effector signaling complex. SLP-76 binds the Tec-family tyrosine kinase, Itk, which phosphorylates SLP-76 at Y173 and PLC-γ1 at Y783. Here we identified Gads Y45 as an additional TCR-inducible, Itk-mediated phosphorylation site. Y45 is found within the N-terminal SH3 domain of Gads, an evolutionarily conserved domain with no known binding partners or signaling function. Gads Y45 phosphorylation depended on the interaction of Gads with SLP-76 and on the preferentially-paired binding of Gads to phospho-LAT. Three Itk-related features, Gads Y45, SLP-76 Y173, and a proline-rich Itk SH3-binding motif on SLP-76, were selectively required for activation of the CD28 RE/AP transcriptional element from the IL-2 promoter, but were not required to activate NFAT. This study illuminates a new regulatory module, in which Itk-targeted phosphorylation sites on two adaptor proteins, SLP-76 and Gads, control the transcriptional response to TCR/CD28 costimulation, thus enforcing the obligatory interdependence of the TCR and CD28 signaling pathways.

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Section: The Itk-targeted Sites On Slp-76 and Gads Are Selectively Rementioning

confidence: 80%

Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Hallumi

Shalah

Lo³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…This is supported by subsequent studies showing also that phosphorylation of tyrosines in SH3 domains themselves can lead to the inhibition of partner binding. Specifically, in a recent study of Abl1 and Abl2 SH3 domains, we have shown that two specific simultaneously-phosphorylated tyrosines hinder ligand binding by sterically blocking the ligand binding groove with the phosphate groups [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding

Tőke

Koprivanacz

Radnai

et al. 2021

Cells

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SH3 domains constitute an important class of protein modules involved in a variety of cellular functions. They participate in protein-protein interactions via their canonical ligand binding interfaces composed of several evolutionarily conserved aromatic residues forming binding grooves for typical (PxxP) and atypical (PxxxPR, RxxK, RKxxY) binding motifs. The calcium/calmodulin-dependent serine protein kinase (CASK)-interacting protein 1, or Caskin1, a multidomain scaffold protein regulating the cortical actin filaments, is enriched in neural synapses in mammals. Based on its known interaction partners and knock-out animal studies, Caskin1 may play various roles in neural function and it is thought to participate in several pathological processes of the brain. Caskin1 has a single, atypical SH3 domain in which key aromatic residues are missing from the canonical binding groove. No protein interacting partner for this SH3 domain has been identified yet. Nevertheless, we have recently demonstrated the specific binding of this SH3 domain to the signaling lipid mediator lysophospatidic acid (LPA) in vitro. Here we report the solution NMR structure of the human Caskin1 SH3 domain and analyze its structural features in comparison with other SH3 domains exemplifying different strategies in target selectivity. The key differences revealed by our structural study show that the canonical binding groove found in typical SH3 domains accommodating proline-rich motifs is missing in Caskin1 SH3, most likely excluding a bona fide protein target for the domain. The LPA binding site is distinct from the altered protein binding groove. We conclude that the SH3 domain of Caskin1 might mediate the association of Caskin1 with membrane surfaces with locally elevated LPA content.

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“…In several cases, the functional consequences have also been investigated. Merő et al presented the first crystal structures of tyrosine-phosphorylated human SH3 domains derived from the Abelson-family kinases ABL1 and ABL2 [ 75 ]. The structures revealed that simultaneous phosphorylation of Y89 and Y134 in ABL1 or the homologous residues Y116 and Y161 in ABL2 induces only minor structural changes.…”

Section: Sh3 Domains Function From Constitutive Through Regulated Protein Binding To Lipid Recognitionmentioning

confidence: 99%

“…Extensive analysis of relevant literature and databases revealed not only that the residues phosphorylated in these model systems are well-conserved in other human SH3 domains, but also that the corresponding tyrosine residues are, in many cases, known phosphorylation sites in vivo. These results suggest that tyrosine phosphorylation of SH3 domains might be a mechanism involved in the regulation of the human SH3 interactome [ 75 ].…”

Section: Sh3 Domains Function From Constitutive Through Regulated Protein Binding To Lipid Recognitionmentioning

confidence: 99%

Novel Roles of SH2 and SH3 Domains in Lipid Binding

Sipeki

Koprivanacz

Takács

et al. 2021

Cells

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Signal transduction, the ability of cells to perceive information from the surroundings and alter behavior in response, is an essential property of life. Studies on tyrosine kinase action fundamentally changed our concept of cellular regulation. The induced assembly of subcellular hubs via the recognition of local protein or lipid modifications by modular protein interactions is now a central paradigm in signaling. Such molecular interactions are mediated by specific protein interaction domains. The first such domain identified was the SH2 domain, which was postulated to be a reader capable of finding and binding protein partners displaying phosphorylated tyrosine side chains. The SH3 domain was found to be involved in the formation of stable protein sub-complexes by constitutively attaching to proline-rich surfaces on its binding partners. The SH2 and SH3 domains have thus served as the prototypes for a diverse collection of interaction domains that recognize not only proteins but also lipids, nucleic acids, and small molecules. It has also been found that particular SH2 and SH3 domains themselves might also bind to and rely on lipids to modulate complex assembly. Some lipid-binding properties of SH2 and SH3 domains are reviewed here.

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Structural insights into the tyrosine phosphorylation–mediated inhibition of SH3 domain–ligand interactions

Cited by 16 publications

References 59 publications

Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Itk promotes the integration of TCR and CD28 costimulation, through its direct substrates, SLP-76 and Gads

Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding

Novel Roles of SH2 and SH3 Domains in Lipid Binding

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