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Immediate Cytokine Responses to Endotoxin: Tumor Necrosis Factor-α and the lnterleukin-1 Family
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Similar to precursor IL-1β (proIL-1β), precursor IL-18 (proIL-18) does not contain a signal peptide required for the removal of the precursor amino acids with subsequent secretion. There are few cytokines and growth factors that do not contain signal peptides, but the precursor forms of these proteins are often fully active (proIL-1α and ciliary neurotrophic factor are active), and processing does not appear to be required for biological activity. However, for IL-1β, the activity of the precursor is exceedingly low, but after cleavage by ICE the mature form is fully active. ICE, also called caspase-1 (72), is the first member of the family of intracellular cysteine proteases cleaving at an aspartic acid residue. The N-terminal amino acid sequence of the secreted form of murine IL-18 (47) was consistent with that following cleavage after an aspartic acid residue, a typical cleavage site for ICE. In fact, this analysis alerted investigators that the cleavage of proIL-18 at the aspartic acid site would likely require ICE (70). Therefore, it was not surprising that ICE cleaved proIL-18 (after the aspartic acid 36) and resulted in the mature and active protein (68,73). In addition to caspase-1, caspase-3 (also known as CPP32) cleaves mature or proIL-18 after aspartic 71 and 76, resulting in inactive peptides (74). As reported for proIL-1β (75), proIL-18 may serve as a negative regulator of Fas-mediated cell death by acting as a sink for the enzymatic activity of caspase-1 and caspase-3. It is caspase-3, however, that is likely to play a greater role in cell death than ICE.
Motilin and Gastric Inhibitory Polypeptide (GIP)
Published in Craig A. Johnston, Charles D. Barnes, Brain-Gut Peptides and Reproductive Function, 2020
Human GIP was isolated by Moody et al. (1984) from postmortem intestinal tissue. Sequence analysis showed that the arginine at position 18 in porcine GIP was substituted by histidine and serine at position 34 by asparagine (Fig. 3). This sequence has been confirmed from cDNAs encoding the human GIP precursor (Takeda et al., 1987). The predicted amino acid sequence showed that the GIP precursor consists of 153 amino acids. The GIP sequence is flanked by 51- and 60-amino acid peptides at the N- and C-termini, respectively. The N-terminus consists of a 21-amino acid signal peptide and a propeptide of 30 amino acids.
Sly disease/β-glucuronidase deficiency/mucopolysaccharidosis VII
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The disorder is transmitted in an autosomal recessive fashion via mutant genes on chromosome 7 [10]. Its incidence has been estimated at one in 300,000 live births in British Columbia [33]. The molecular defect is in the enzyme β-glucuronidase. (EC 3.2.1.31) [1, 34]. Cultured fibroblasts from patients accumulate sulfated mucopolysaccharide when incubated with 35SO4, and this abnormality is corrected by the addition of bovine liver β-glucuronidase to the medium [34]. Identity of the corrective factor and the glucuronidase was demonstrated by coelectrophoresis in polyacrylamide gel. Virtually complete deficiency has been demonstrated with a variety of synthetic substrates in leukocytes and in fibroblasts [34]. It has also been detected in serum [18]. The enzyme is a tetramer of 75 kDa subunits [35]. It is synthesized as a precursor protein and processed at the carboxyl end by the loss of the signal peptide [34]. Immunochemical studies have indicated the presence of cross-reacting material (CRM) in patients with the disease [36]. The measurement of enzyme activity has not correlated well with the degree of severity of phenotype.
Pentapeptide modified ethosomes for enhanced skin retention and topical efficacy activity of indomethacin
Published in Drug Delivery, 2022
Jiangxiu Niu, Ming Yuan, Hongying Li, Yao Liu, Liye Wang, Yanli Fan, Yansong Zhang, Xianghui Liu, Lingmei Li, Jingxiao Zhang, Chenyu Zhao
Lysine-threonine-threonine-lysine-serine is a short peptide derived from collagen hydrolysis and its more stable form is palmitoyl-pentapeptide (Pal-KTTKS), which is a derivative of KTTKS combined with palmitoyl. It is easy to penetrate the SC of the skin due to its good interaction with the skin. KTTKS is a signal peptide in skin tissue, it can be recognized and bound by signal recognition particles (SRP) in skin tissues, and promote the synthesis of matrix proteins, especially collagen, by increasing the activity of stromal cells (Tałałaj et al., 2019). Signal peptides can be used to modify nano drug delivery systems to improve the functionality of preparations (Bae et al., 2021). In light of this, KTTKS might be used in nano-drug delivery systems to improve the intradermal retention of the drug in the lesion site through the interaction between KTTKS and proteins in the skin, thus enhancing the therapeutic effect.
A novel frameshift GP1BB mutation causes autosomal dominant macrothrombocytopenia with decreased vWF receptor expression but normal platelet aggregation
Published in Platelets, 2022
Caitlin Dunstan-Harrison, Ian M. Morison, Elizabeth C. Ledgerwood
Whole-exome sequencing of subjects II-4, III-1 and III-2 identified a novel frameshift mutation in GP1BB, c.327dupG:p.Arg110fs, which was confirmed by PCR sequencing. The only other variant identified in genes associated with macrothrombocytopenia was a synonymous variant in MYH9 (c.3216G>A:p.Ala1072Ala). The c.327dupG:p.Arg110fs variant, classified as pathogenic variant strong 1 by the ACGM criteria [17], has not previously been reported as causing macrothrombocytopenia and is not present in the ExAC or dbSNP variant databases. Duplication of a G in the codon for Arg110 produces an alternative reading frame that encodes a protein that is 101 amino acids longer than wild type (Figure 1C–E). Predicted to be pathogenic by MutationTaster [18], this variant abolishes the transmembrane domain and normal stop codon and leads to a novel C-terminal domain. In addition, Cys147, which normally forms a disulfide bond with GPIbα, is no longer present. Transmembrane tendency of wildtype (WT) and p.Arg110fs GPIbβ was analysed by the ExPASy-ProtScale online tool [19] (Figure 1F). In WT, as expected, there are two regions with a score >0, the signal peptide and the transmembrane domain. The predicted mutant protein retains the signal peptide, but the novel C-terminus (residues 110–307) has no transmembrane-forming tendency, making it highly unlikely that the protein will be located in the membrane.
Immunoinformatics driven construction of multi-epitope vaccine candidate against Ascaris lumbricoides using its entire immunogenic epitopes
Published in Expert Review of Vaccines, 2021
Rimanpreet Kaur, Naina Arora, Suraj Singh Rawat, Anand Kumar Keshri, Neha Singh, Sumit Kumar Show, Pramod Kumar, Amit Mishra, Amit Prasad
The membrane proteins and excretory/secretory proteins are the first parasitic antigens that interact with the host immune system and induce an immunological response (activation/suppression). The signal peptides present on the N-terminal of proteins determine their fate to mark as secretory protein or to be located on the cell membrane. The Signal P 5.0 server (http://www.cbs.dtu.dk/services/SignalP/index.php) was used for this purpose [19]. The signal peptide prediction alone does not define the exact location of the proteins, so other servers were also used to find the membrane proteins, Deeploc server (http://www.cbs.dtu.dk/services/DeepLoc-1.0/index.php) and WolfPsort (https://wolfpsort.hgc.jp/), it predicted the subcellular localizations of proteins in the cell and the common membrane proteins thus identified were used for further analysis [20,21].