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JAK-STAT pathway: Testicular development, spermatogenesis and fertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
In JAK-STAT signaling, nonreceptor tyrosine kinase is the main class of receptors. These are single-membrane receptors with no intrinsic tyrosine kinase activity. Their intracellular cytoplasmic tails are associated with JAK, which gets phosphorylated on ligand binding and recruits STAT for further extending pathway function. In mammals, the subfamilies are gp130 family receptor, IL-2 family receptors, gp140 family receptors and growth hormone family receptors (10,11). In Drosophila, Domeless is the only known receptor that is encoded by the Dome gene (20) and also named as Master of Marelle (MOM) by another group (21). These nonreceptor tyrosine kinase receptors have a cytoplasmic membrane proximal domain through which they associate with tyrosine kinase-JAK (26). Domeless is a membrane-associated protein. Its extracellular domain consists of five fibronectin type III domains (FNIII). Out of these, two show similarity to the cytokine binding module of vertebrate cytokine receptor family I, which includes four conserved cysteine residues in the N-terminal domain and an incomplete WSXWS motif in the C-terminal domain (20) (Figure 15.2).
Tyrosine Phosphatases as New Treatment Targets in Acute Myeloid Leukemia
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
I. Hubeek, K. Hoorweg, J. Cloos, Gertjan J. L. Kaspers
The first category is the largest family and consists of the class I cysteine-based PTPs. The 38 strictly tyrosine-specific “classical PTPs” belong to this family and can be further divided into trans-membrane, receptor-like PTPs (RPTPs), and the intracellular, nonreceptor PTPs (NRPTPs) (15). The RPTPs have a single trans-membrane and variable extracellular domain. The intracellular parts of most of the RPTPs contain two tandem PTP domains, D1 and D2, with most of the catalytic activity resident in D1. In many cases, the extracellular domains include immunoglobulin like and fibronectin type III domains. These domains are similar to the extracellular domains of cellular adhesion molecules (16). NRPTPs have striking structural diversity and often contain sequences that target them to specific subcellular locations or enable their binding to specific proteins (17). The 61 dual specificity phosphatases (DSPs), or VH-1 like enzymes, also belong to the class I cysteine-based PTPs. DSPs are able to dephosphorylate serine and threonine residues in their protein substrates in addition to tyrosine residues. This group can be further divided into seven subgroups. MKPs are specific for the mitogen-activated protein kinases (MAPKs) (18,19); atypical DSPs (20) include 19 poorly characterized enzymes; phosphatase and tensin homologs (PTENs) and myotubularins dephosphorylate the D3-phosphate of inositol phospholipids (21); PRLs and slingshots are poorly understood; and CDC14s are involved in dephosphorylating cyclin-dependent kinases (Cdks) and exit mitosis (22).
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Monobodies are the protein scaffolds based on Fibronectin type III domain. Fibronectin is a large protein that interacts with the extracellular matrix proteins and regulates cell-cell communication. Structurally, it is a large protein containing two 250 kD subunits connected by disulfide bridges. These subunits contain the repeats of three domains (type I, II, III). The first monobody was engineered using the tenth repeat of type III domain of Fibronectin (FNfn10) against ubiquitin using phage display system. FNfn10 is devoid of disulfide bonds, and also contains 7 β-strands and 3 surface loops that can be used to add diversity to the monobodies. Their structural simplicity makes them compatible with any screening method such as phage display, yeast two-hybrid system, and peptide-ribonucleic acid. They can be expressed in large quantities in bacteria and are highly thermo stable (Koide and Koide, 2007). Such properties of monobodies make them ideal candidates for therapeutic protein scaffolds. Monobodies have been engineered for the numerous proteins including EGFR (Hackel et al., 2012), IL-23 (Tang et al., 2012), Ableson (Abl) kinase SH2 domain (Wojcik et al., 2010), etc.
An emerging role of interleukin-23 in rheumatoid arthritis
Published in Immunopharmacology and Immunotoxicology, 2019
Na Yuan, Guimei Yu, Di Liu, Xiancheng Wang, Ling Zhao
IL-23R has three domains: domain 1 (D1), domains 2 (D2), and domain 3 (D3). D1 is located at N-terminal region and structurally, it resembles immunoglobins (Ig). D2 and D3 are fibronectin type III domains and, these consititute a cytokine-binding module (CBM). The receptor also has a long stalk segment, transmembrane structure and cytoplasmic regions [23,27]. Structurally, IL-12Rβ1 subunit does not possess D1. However, it contains CBM (D2 and D3), transmembrane and cytoplasmic regions. Since D1 is absent in IL-12Rβ1, therefore, p19 (a structural unit of IL-23) interacts with CBM of IL-23R via site II. In contrast, p40 interacts with IL-12Rβ1 via site III. It has been shown that the binding of IL-23 to the functional IL-23 receptor (IL-23R-IL-12Rβ1) follows the ‘site I–II–III’ paradigm. The p19 portion of IL-23 binds to the p40 through site I and to the IL-23R subunit through site II. On the other hand, p40 portion of IL-23 binds to the IL-12Rβ1 subunit through site III (Figure 2). Furthermore, it has been documented that p40 alone acts as IL-23 antagonist and binding of p19 at site II is very essential for IL-23 signaling [28].
Myostain is involved in ginsenoside Rb1-mediated anti-obesity
Published in Pharmaceutical Biology, 2022
Hong-Shi Li, Jiang-Ying Kuang, Gui-Jun Liu, Wei-Jie Wu, Xian-Lun Yin, Hao-Dong Li, Lei Wang, Tao Qin, Wen-Cheng Zhang, Yuan-Yuan Sun
Fibronectin type III domain-containing 5 (FNDC5), a well-defined myokine and also identified as an adipokine, has a critical role in the modulation of metabolism and protection against obesity. These important functions are mediated by irisin, a secretory peptide produced from proteolytic processing of FNDC5 (Rabiee et al. 2020). It was found that MSTN may be the upstream regulatory molecule of FNDC5 (Ge et al. 2017). However, whether MSTN is involved in weight loss caused by Rb1 has not been reported.
Exome sequencing identified five novel USH2A variants in Korean patients with retinitis pigmentosa
Published in Ophthalmic Genetics, 2023
SeungHee Jung, Young Chan Park, DongHee Lee, SiYeon Kim, Sang-Mo Kim, YoungJin Kim, DongHyun Lee, JaeJoung Hyun, InSong Koh, Jong-Young Lee
Among the five novel variants, one missense variant, c.12855 G>C, is located on exon 63. This variant causes the same amino acid change at the same position as c.12855 G>T, which has been reported to be a pathogenic variant in ClinVar and LOVD. It was predicted to have a deleterious effect using in silico software (Table 1). Structural differences in the fibronectin type III domain were predicted between the wild type and mutant type due to this variant (Figure 2a).