Fc Receptors
Maurizio Zanetti, J. Donald Capra in The Antibodies, 1999
Signals that are transduced by FcR are triggered following the binding of the Fc portion of antibodies of specific classes which bind, even more specifically, with antigens via their Fab portions. A similar immunological specificity for their ligands is also a feature of other immunoreceptors. Interestingly, the exquisite specificity of extracellular ligand-receptor interactions progressively degenerates as intracellular signals are propagated in cells. The immunological specificity of immunoreceptors is substituted for that of SH2 domains: phosphorylated ITAMs primarily recruit SH2 domain-bearing protein tyrosine kinases and adaptors, whereas phosphorylated ITIMs recruit SH2 domain-bearing phosphatases. One step further, the specificity of SH2 domains is substituted for that of enzymes for their substrates. This degenerescence may confer a fundamental property to FcR and other immunoreceptors. Indeed, metabolic chains activated following FcR aggregation are the same as those which are activated following the aggregation of other receptors. As a consequence, signals generated simultaneously on the same cell by FcR, cytokine receptors, hormone receptors or growth factor receptors, among others, can converge, synergize or antagonize, cooperate, integrate, and thereby ensure homeostasis.
Molecular Mechanisms Controlling Immunoglobulin E Responses
Thomas F. Kresina in Immune Modulating Agents, 2020
It is now recognized that other cytokines share this general model of signal transduction, and that at least seven members of the ST AT family exist (Stats 1, 2, 3, 4, 5a, 5b, and 6). These proteins share significant homology over several functional domains. The greatest homology is observed within the regions of the SH2 and SH3 motifs and the deoxyribonucleic acid (DNA) binding domain (reviewed in Ref. 60) (Figure 2). Nonetheless, different cytokines/ligands are able to activate different STATs with great specificity. Specificity of signaling is achieved at the level of the cytokine receptor/STAT interaction and not regulated by the particular JAKs involved. This specificity results from the interaction between the SH2 domain of the STAT and motifs on the receptor chains that, after activation by ligand, contain phosphorylated tyrosine residues [61]. This interaction allows the recruitment of different STATs into different receptor complexes.
Protein Phosphorylation
Enrique Pimentel in Handbook of Growth Factors, 2017
Immediately amino-terminal to the kinase domain there is a sequence of approximately 100 residues that is present in all tyrosine kinases, either localized in the cytoplasm or having a transmembrane region. This region, termed SH2, is not essential for catalytic activity but may have a role in directing the cellular actions of the kinase domain by determining specific interactions of the enzyme with cell components. The three-dimensional structure of the SH2 domain of the v-Src oncoprotein (residues 144-249) has been determined by X-ray crystallography.49 The c-Src and c-Abl proteins share an additional noncatalytic domain of 50 residues, SH3, located amino-terminal to SH2. Elements similar to SH2 and SH3 are present in other cellular and viral proteins, including the Ras GTPase-activating protein (GAP), protein-tyrosine phosphatases, phospholipase C-γ, and the regulatory subunit of phosphatidyinositol 3-kinase (PI 3-kinase).52 Binding of a fusion protein construct containing two SH2 domains from phospholipase C-γ to the EGF receptor is absolutely dependent on EGF-induced tyrosine phosphorylation of the receptor.53 The v-Crk oncoprotein, which is the product of the v-crk oncogene contained in the avian sarcoma virus (AVS) CT10, as well as the normal cellular counterpart of this gene, the c-Crk protein, consist mainly of SH2 and SH3 regions that are involved in the recognition of phosphotyrosines contained in cellular proteins.54,55 The 35-kDa Crk protein does not contain a catalytic domain and is expressed in CEF cells and embryonic chicken tissues.
Understanding SOCS protein specificity
Published in Growth Factors, 2018
Edmond M. Linossi, Dale J. Calleja, Sandra E. Nicholson
The first point of difference from the canonical SH2 domain structure is the presence of an additional α-helix immediately N-terminal to the SOCS-SH2 domain, termed the extended SH2-subdomain (ESS) (Yasukawa et al., 1999) (Figure 2(B–D)). This forms part of the ‘modular’ SOCS-SH2 domain, making direct contact with the BG loop and other residues that form the phosphopeptide binding pocket (Babon et al., 2006). The ESS also contributes to a second unique binding surface present in SOCS1 and SOCS3 (discussed below) and is thought to provide some stability between the hydrophobic interfaces of the SOCS box and SH2 domain (Bullock et al., 2006, 2007). A number of SH2 domain proteins contain adjacent domains whose proximity or interaction with the SH2 domain regulates protein function, contributing to substrate specificity, affinity or intermolecular interactions (Liu et al., 2012). Notably, the SH2 domains of STAT1b, STAT3 and Cbl also contain an additional α-helix (as part of adjoining domains or linkers), although in each of these the α-helix is positioned differently to the ESS of the SOCS (Babon 2006; Bullock et al., 2007).
Design, synthesis, and in vitro evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Patrik Oleksak, Miroslav Psotka, Marketa Vancurova, Olena Sapega, Jana Bieblova, Milan Reinis, David Rysanek, Romana Mikyskova, Katarina Chalupova, David Malinak, Jana Svobodova, Rudolf Andrys, Helena Rehulkova, Vojtech Skopek, Pham Ngoc Lam, Jiri Bartek, Zdenek Hodny, Kamil Musilek
The STAT3 protein structure is characterised by four domains involved in oligomerisation, binding to DNA, and transactivation activity, and a Src homology 2 (SH2) domain mediating phosphorylation-dependent dimerisation. The SH2 domain contains tyrosine 705 (Y705), which is phosphorylated in response to extracellular signalling by kinases of the Jak and Src families. STAT3 proteins with phosphorylated Y705 (pY705) form dimers via reciprocal binding of SH2 domains and they are further translocated into the nucleus to bind to specific DNA response elements. STAT3 are both activators and repressors of hundreds of genes, including cell cycle regulators MYC and CCND1 and anti-apoptotic BCL-2 family genes BCL2, BCL2L2 (BCL-W), BCL2L1 (BCL-XL), MCL1, and BIRC5 (survivin; reviewed in refs.4,5).
New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ahmed Elkamhawy, Eslam M. H. Ali, Kyeong Lee
The strcuture of Lck has the typical backbone found in all members of the Src kinase family (Figure 1); an N-terminal site (SH4 domain), SH3 and SH2 domains, a catalytic domain at the carboxy terminal (SH1 domain), and a short C-terminal tail17–19. The C-terminal lobe contains the activation loop (alpha-helix) which forms the phosphorylation site. Both SH2 and SH3 domains are folded to be involved in protein-protein interactions responsible for the regulation of Lck activity and signal transmission; while the main function of SH2 domain is to regulate interactions with phosphotyrosine containing elements, the SH3 domain regulates interactions with proline rich elements. The SH4 domain contains a glycine and two cysteine residues, which are myristoylated and palmitoylated, respectively, to target Lck to the plasma membrane.
Related Knowledge Centers
- Alpha Helix
- Beta Sheet
- Oncogene
- Protein Domain
- Receptor Tyrosine Kinase
- Signal Transduction
- Tyrosine
- Proto-Oncogene Tyrosine-Protein Kinase Src
- Protein–Protein Interaction
- Signal Transducing Adaptor Protein