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Pregnancy-Related Proteins Detected by Immunochemical or Physicochemical Methods
Published in Gábor N. Than, Hans Bohn, Dénes G. Szabó, Advances in Pregnancy-Related Protein Research, 2020
Isolation and purification of placental protein 10 (PP10) has been reported in 1979.89 Recently it was found that PP10 is immunochemically identical with plasminogen activator inhibitor 2 (PAI-2).90 Sequence analysis also showed that the amino acid sequence is the same for PAI-2 and PP10. PP10 freshly prepared showed PAI-2 activity, whereas preparations stored in lyophilized form had lost this activity by cleavage of an Arginin-Threonine bond in the PAI-2 molecule.
Gene Expression and Function of Plasminogen Activator lnhibitor-1
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Daniel A. Lawrence, David Ginsburg
The reactive center region of PAI-1 has been the subject of extensive mutational analysis.36-38,131,141,142 These studies have generally demonstrated the importance of the P1 bait residue in inhibitor function, with the surrounding amino acids playing a less critical role. York and coworkers37 and Sherman et al.38 performed random mutagenesis of the P3, P2, P1 residues and the P1, P1′ residues, respectively, and clearly demonstrated that either arginine or lysine at P1 is essential for PAI-1 to function as an effective inhibitor of u-PA. These studies also demonstrated that the residues surrounding P1 can modulate PAI-1 inhibitor activity by up to two orders of magnitude and can also alter target protease specificity. P1′ was surprisingly tolerant of amino acid substitutions with the exception of proline, which resulted in near total loss of function.38 This is most likely due to a conformational change in the reactive center scissile bond. In another study an 18-amino acid segment of PAI-1, encompassing most of the reactive center loop, was replaced with the same region from plasminogen activator inhibitor-2, antithrombin III, or with a SERPIN consensus sequence.141 This report demonstrated that most of the requirements for PAI-1 specificity, apart from the P1 residue, he outside of the reactive center loop sequence. All three chimeras remained very efficient inhibitors of t-PA and u-PA and the antithrombin III chimera was not significantly improved as an inhibitor of thrombin. Furthermore, it was shown that the specific sequence of the reactive center loop, the region inserted into β-sheet A in the latent PAI-1 structure (see discussion above), was not critical for the conversion between the active and latent conformations of PAI-1 since all the inhibitors had similar half-lives. This observation suggests that loop insertion is dependent more on the flexibility of β-sheet A than on the specific amino acid residues in the loop. Finally, this study also demonstrated that binding to vitronectin was not affected by these substitutions in the reactive center loop. The P4′ and P5′ residues on the C-terminal side of the reactive center bond have also been replaced; however, these changes had only a small effect on PAI-1 activity.142
Role of protein deimination in cardiovascular diseases: potential new avenues for diagnostic and prognostic biomarkers
Published in Expert Review of Proteomics, 2021
Liqun Mao, Rowann Mostafa, Esra Ibili, Justyna Fert-Bober
Similarly, a study by Lai et al. showed that the protein expression of PAD2 and PAD4 increased markedly during the differentiation of monocytes into macrophages, and PAD activation correlated to increased citrullination of certain intracellular proteins, including histone H3 and plasminogen activator inhibitor-2 (PAI-2) [83]. Vice versa, decreased expression of PAD2 and PAD4 was showed to suppress the protein levels of H3Cit and citrullinated PAI-2. PAI-2, a serine protease inhibitor in the serpin superfamily, is a coagulation factor that inhibits tissue plasminogen activator and urokinase plasminogen activator. As one of the most upregulated proteins in activated monocytes and macrophages, it can be considered a stress protein. Notably, the citrullination of PAI-2 reduced its binding ability to proteasome subunit β type-1 (PSMB1) and alternated the function of proteasome. The increase in PAI-2 expression by PAD2 induced the production and secretion of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) [83]. Noteworthy, the addition of PAD inhibitors significantly suppressed the secretion of cytokines TNF-α, IL-1β, and IL-6 from the differentiated macrophages without affecting cell viability or the expression level of PAD2 or PAD4 [83]. The same group latter showed that in differentiated macrophages, in addition to IL-1β and TNF-α, PAD2 also promoted the production of IL-6, apoptosis through activation of caspase-2, −3, and −9, and enhanced cell adhesion through FAK, paxillin, and p21-activated kinase 1 (PAK1) [84].
Radiation induced apoptosis and pulmonary fibrosis: curcumin an effective intervention?
Published in International Journal of Radiation Biology, 2020
Shilpa Johnson, Sadiya B. Shaikh, Fatheema Muneesa, Barki Rashmi, Yashodhar P. Bhandary
uPA is a serine protease, which mainly involves in the extravascular proteolysis and tissue remodeling. The enzyme is synthesized as pro-uPA by the lung epithelial cells of which the primary physiological substrate is a zymogen called plasminogen (Kasai et al. 1985; Shetty and Idell 2000). Pro-uPA is cleaved by trace amount of plasmin (Kasai et al. 1985; Shetty and Idell 2000) and activated uPA in turn, cleaves plasminogen at a specific Arg-Val residue to convert it into active plasmin. Activation of plasmin triggers a proteolytic cascade that involves in the extracellular matrix degradation and cell migration (Shetty and Idell 2006). The alveolar epithelial cells also synthesize another protein, which is a cell membrane receptor for uPA. uPA receptor, uPAR, is a multi-domain glycoprotein anchored to the cell membrane with a glycosylphosphatidylinositoltail and expressed on the surface of the cell (Shetty and Idell 2001). Studies show that uPA-uPAR relationship mediates matrix remodeling. Evidence has been reported to prove the role of uPA in regulating lung epithelial cell apoptosis through elaboration of p53 (Kasai et al. 1985; Shetty et al. 2007). The major inhibitors of urokinase are the serpins, PAI-1 and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. PAI-1 expression is increased in lung tissues of patients with pulmonary fibrosis (Marudamuthu, Shetty, et al. 2015). Expression of these fibrinolytic proteins by the alveolar epithelium involves post-transcriptional regulation (Idell 2003). p53, a tumor suppressor protein, also regulates fibrinolysis through promoter transactivation of PAI-1. The study unraveled the mechanism of interaction between p53 and uPAR. uPA regulates p53 in a concentration-dependent manner and p53 regulates the expression of uPAR gene. An earlier study has shown that p53 expression destabilizes uPAR mRNA in H1299 cells, that is, suppression of p53 increases uPAR mRNA stability (Shetty et al. 2007).