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Wiskott–Aldrich Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Structurally, WASP consists of five domains: WH1: WASP homology 1 or EVH1, for ENA/VASP homology 1, which binds to a proline repeat motif in WASP-interacting protein (WIP) and mediates a molecular interaction critical for keeping a stable and autoinhibited WASP conformationB: Basic domain, which binds to the phosphoinositide PIP2 (phosphatidylinositol-4,5-biphosphate) for the activation of WASPGBD: GTPase binding domain, which interacts with VCAPPP: Polyproline domain, which contains several sites for binding of Src homology 3 (SH3) domainVCA: Verprolin-homology–cofilin homology domain–acidic region, which forms the actin-nucleating region of WASP) [4–6]
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Fynomers are the protein scaffolds designed based on the SH3 domain of Fyn enzyme. Fyn enzyme is a tyrosine kinase (belongs to Src family) containing 5 anti-parallel β-strands connected by two loops (Musacchio et al., 1992; Musacchio et al., 1994). Src domain involves in interaction with many proteins associated with cell signaling, cytoskeleton structures, and membrane receptors. Hence, efforts are being made to add diversity to the fynomers by mutagenesis in the two flexible loops. Fyn SH3 domains are also devoid of cysteine residues, hence do not form disulfide bonds and therefore can be expressed efficiently in bacteria. Additional features of higher stability and their occurrence in monomeric form makes fynomers potent therapeutic scaffolds. Fynomers known as 2C1, specific to human IL-17A were designed. They bind to IL-17A with nano-molar affinity. Continuous efforts are being made to fuse the fynomers to antibodies to make them bi-specific or tri-specific or increase their binding affinity to the target protein. 2C1 was fused to the Fc region of antibody using a four amino acid linker. The fynomer-Fc fusion had shown pico-molar binding affinity to IL-17A. Hence, these fusion constructs of fynomers with 100 fold improvement in inhibition of IL-17A, represent the ideal drug candidates for treating IL-17A mediated diseases (psoriasis, psoriatic arthritis and rheumatoid arthritis, etc.) (Silacci et al., 2014). Bispecific FynomAb COVA208 has been designed that reduced the levels of HER2, HER3, and EGFR and thereby showed strong inhibitory action on the downstream signaling of HER2 pathway (Brack et al., 2014).
Guanosine Triphosphate-Binding Proteins
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
In contrast to the positive regulation of Ras protein activity by GNRF, Ras activity is negatively regulated by a GTPase-activating protein (GAP), which is localized in the cytoplasm and enhances the GTPase activity of c-Ras proteins.130 Thus, Ras activity is determined by a balance between the positive action of GNRF and the negative action of GAP, as depicted in Figure 5.1. GAP is ubiquitous in higher eukaryotes and is essential for proper Ras biological activity.131 GAP interacts with the effector binding domain of Ras and catalyzes the conversion of Ras-GTP to Ras-GDP so that this reaction proceeds at rates more than 100 times higher than intrinsic rates. Binding of GAP to GTP induces translocation of the Ras-GTP complex from the cytosol to the plasma membrane and stimulates the weak intrinsic GTPase activity of normal c-Ras proteins, thereby promoting the return of Ras to an inactive, GDP-bound state. Thus, GAP is a negative regulator of normal Ras proteins.132 Expression of GAP in NIH/3T3 cells can suppress neoplastic transformation induced by normal c-H-ras gene, but does not inhibit transformation caused by the v-ras oncogene.133 The carboxyl-terminal domain of the GAP protein is responsible and sufficient for the interaction of GAP with normal cellular proteins and for stimulating their GTPase activities. The amino-terminal region of GAP contains SH2 and SH3 domains that allow tight binding of GAP to the receptors for PDGF, EGF, and insulin, and the SH3 domain of GAP is essential for signal transduction.134 The EGF receptor phosphorylates GAP at one site in vitro, and GAP remains firmly bound to the receptor at physiological salt concentrations.135 The EGF receptor phosphorylates the human GAP protein at Tyr-460, a residue adjacent to GAP SH2 domains.136 The fact that GAP is phosphorylated by diverse tyrosine kinases reinforces the concept of the existence of important biochemical linkages between the Ras and tyrosine kinase signaling pathways. A phospholipid-associated cytoplasmic protein may be involved in counteracting GAP activity, thus increasing the biological activity of Ras and stimulating cell proliferation.137 The gene of the GAP protein is located on human chromosome 5q13-q15.138
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.
The e1a3 BCR-ABL1 fusion transcript in Philadelphia chromosome-positive acute lymphoblastic leukaemia: a case report
Published in Hematology, 2023
The deletion of ABL1 exon a2 from the BCR-ABL1 fusion transcript results in a protein that lacks two-thirds of the Src homology 3 (SH3) domain [6]. The SH3 domain is considered to play a negative regulatory role in the kinase domain (SH1); the lack of an SH3 domain might result in a more aggressive form of Ph+ leukaemia [13,15]. In contrast, the SH3 domain is required as a signal transducer and activator of transcription 5 activation by BCR–ABL protein, leading to full leukemogenesis [17]. Therefore, deletion of the SH3 domain might induce a less progressive clinical course.
Role of co- and post-translational modifications of SFKs in their kinase activation
Published in Journal of Drug Targeting, 2020
Mei-Lian Cai, Meng-Yan Wang, Cong-Hui Zhang, Jun-Xia Wang, Hong Liu, Hong-Wei He, Wu-Li Zhao, Gui-Ming Xia, Rong-Guang Shao
The SH3 domain is a protein domain consisting of approximately 60 residues. This region mediates a variety of roles, such as substrate recognition [75,76], membrane localisation, and negative regulation of kinase activity [77]. The SH3 domain contains three hydrophobic pockets that are necessary for ligand binding. Tyrosine phosphorylation within these hydrophobic pockets plays a significant role in binding capacity with ligands [78].