Current Protein and Peptide Science - Volume 24, Issue 4, 2023

Golgi SNARE, with a size of 28 kD (GS28), is a transmembrane protein and mainly localizes to the Golgi apparatus. It is considered a core part of the Golgi SNARE complex in the Endoplasmic Reticulum (ER)-Golgi transport and regulates the docking and fusion of transport vesicles effectively. In recent years, increasing studies have indicated that various intracellular transport events are regulated by different GS28-based SNARE complexes. Moreover, GS28 is also involved in numerous functional signaling pathways related to different diseases via interacting with other SNARE proteins and affecting protein maturation and secretion. However, the precise function of GS28 in different disease models and the regulatory network remains unclear. In this review, we mainly provide a concise overview of the function and regulation of GS28 in vesicle trafficking and diseases and summarize the signaling pathways regarding potential mechanisms. Although some critical points about the significance of GS28 in disease treatment still need further investigation, more reliable biotechnical or pharmacological strategies may be developed based on a better understanding of the diverse role of GS28 in vesicle trafficking and other biological processes.

Anti-apoptotic and anti-autophagic Bcl-2 homologues commonly contain a hydrophobic groove in which the BH3 domain is accommodated. The BH3 domain is usually considered a feature of Bcl-2 family members; however, it has also been found in various non-Bcl-2 family proteins. Although interactions among Bcl-2 family members have been extensively investigated and highlighted, those mediated by the BH3 domain of non-Bcl-2 family proteins have not been the focus of substantial research. In this review, the author conducted a structural analysis of Bcl-xL complexed with the BH3 domain of four non-Bcl-2 family proteins, Beclin 1, SOUL, TCTP, and Pxt1, at an atomic level. Although the overall Bcl-xL-binding modes are similar among these proteins, they are characterized by limited sequence conservation of the BH3 consensus motif and differences in residues involved in complex formation. Based on the structural analysis, the author suggests that more “undiscovered” BH3 domain-containing proteins might exist, which have been unidentified due to their limited sequence conservation but can bind to Bcl-2 family proteins and control apoptosis, autophagy, or other biological processes.

This article provides a comprehensive review of several subclasses of metallo-type peptidases expressed by the main clinically relevant protozoa, including Plasmodium spp., Toxoplasma gondii, Cryptosporidium spp., Leishmania spp., Trypanosoma spp., Entamoeba histolytica, Giardia duodenalis, and Trichomonas vaginalis. These species comprise a diverse group of unicellular eukaryotic microorganisms responsible for widespread and severe human infections. Metallopeptidases, defined as hydrolases with activity mediated by divalent metal cation, play important roles in the induction and maintenance of parasitic infections. In this context, metallopeptidases can be considered veritable virulence factors in protozoa with direct/indirect participation in several key pathophysiological processes, including adherence, invasion, evasion, excystation, central metabolism, nutrition, growth, proliferation, and differentiation. Indeed, metallopeptidases have become an important and valid target to search for new compounds with chemotherapeutic purposes. The present review aims to gather updates regarding metallopeptidase subclasses, exploring their participation in protozoa virulence as well as investigating the similarity of peptidase sequences through bioinformatic techniques in order to discover clusters of great relevance for the development of new broad antiparasitic molecules.

Background: The brain melanocortin system regulates numerous physiological functions and kinds of behavior. The agouti protein inhibits melanocortin receptors in melanocytes. The lethal yellow (A^Y) mutation puts the Agouti gene under the control of the Raly gene promotor and causes the agouti protein expression in the brain. In the present article, we investigated the effects of the A^Y mutation on brain mRNA levels of Agouti, Raly, and melanocortin-related genes such as Agrp, Pomc, Mc3r, Mc4r, and their relationship to behavior. Methods: The experiment was performed on 6-month-old males and females of A^Y/a and a/a (control) mice. Anxiety and obsessive-compulsive behavior were studied in elevated plus-maze and marble- burying tests. The mRNA levels were quantified by qPCR. Results: A^Y mutation caused anxiety in males and obsessive-compulsive behavior in females. Positive correlation between Agouti and Raly genes mRNA levels were shown in the hypothalamus, hippocampus, and frontal cortex in A^Y/a mice. Reduced RNA concentrations of Mc3r and Mc4r genes were found respectively in the hypothalamus and frontal cortex in A^Y/a males. The Raly gene expression positively correlates with mRNA concentrations of the Mc3r gene in the hypothalamus and the Mc4r gene in the hypothalamus and frontal cortex. Conclusion: Possible association of obsessive-compulsive behavior with reduced Raly, Mc3r, or Mc4r gene expression is suggested.

Background: Many N-terminal acetyltransferases (NATs) play important role in the posttranslational modifications of histone tails. Research showed that these enzymes have been reported upregulated in many cancers. NatD is known to acetylate H4/H2A at the N-terminal. During lung cancer, this enzyme competes with the protein kinase CK2α and blocks the phosphorylation of H4 and, acetylates. It also, we observed that H4 has various mutations at the N-terminal and we considered only four mutations (S1C, R3C, G4D and G4S) to study the impacts of these mutations on H4 binding with NatD using MD simulation. Objective: Our main objective in this study was to understand the structure and dynamics of hNatD under the influence of WT and MT H4 histones bindings. The previous experimental study reported that mutations on H4 N-terminus reduce the catalytic efficiency of N-Terminal acetylation. But here, we performed a molecular- level study thus, we can understand how these mutations (S1C, R3C, G4D and G4S) cause significant depletion in catalytic efficiency of hNatD. Methods: Purely computational approaches were employed to investigate the impacts of four mutations in human histone H4 on its binding with the N-α-acetyltransferase D. Initially, molecular docking was used to dock the histone H4 peptide with the N-α-acetyltransferase. Next, all-atom molecular dynamics simulation was performed to probe the structural deviation and dynamics of N-α-acetyltransferase D under the binding of WT and MT H4 histones. Results: Our results show that R3C stabilizes the NatD whereas the remaining mutations destabilize the NatD. Thus, mutations have significant impacts on NatD structure. Our finding supports the previous analysis also. Another interesting observation is that the enzymatic activity of hNatD is altered due to the considerably large deviation of acetyl-CoA from its original position (G4D). Further, simulation and correlation data suggest which regions of the hNatD are highly flexible and rigid and, which domains or residues have the correlation and anticorrelation. As hNatD is overexpressed in lung cancer, it is an important drug target for cancer hence, our study provides structural information to target hNatD. Conclusion: In this study, we examined the impacts of WT and MTs (S1C, R3C, G4D and G4S) histone H4 decapeptides on their bindings with hNatD by using 100 ns all-atom MD simulation. Our results support the previous finding that the mutant H4 histones reduce the catalytic efficiency of hNatD. The MD posttrajectory analyses revealed that S1C, G4S and G4D mutants remarkably alter the residue network in hNatD. The intramolecular hydrogen bond analysis suggested that there is a considerable number of loss of hydrogen bonds in hNatD of hNatD-H4_G4D and hNatD-H4_G4S complexes whereas a large number of hydrogen bonds were increased in hNatD of hNatD-H4_R3C complex during the entire simulations. This implies that R3C mutant binding to hNatD brings stability in hNatD in comparison with WT and other MTs complexes. The linear mutual information (LMI) and Betweenness centrality (BC) suggest that S1C, G4D and G4S significantly disrupt the catalytic site residue network as compared to R3C mutation in H4 histone. Thus, this might be the cause of a notable reduction in the catalytic efficiency of hNatD in these three mutant complexes. Further, interaction analysis supports that E126 is the important residue for the acetyltransferase mechanisms as it is dominantly found to have interactions with numerous residues of MTs histones in MD frames. Additionally, intermolecular hydrogen bond and RMSD analyses of acetyl-CoA predict the higher stability of acetyl-CoA inside the WT complex of hNatD and R3C complex. Also, we report here the structural and dynamic aspects and residue interactions network (RIN) of hNatD to target it to control cell proliferation in lung cancer conditions.

Background: Osteoporosis is a systemic bone disease with low bone mass, destruction of bone microstructure, and increased bone fragility. Gender and metabolic status are well-known risk factors for osteoporosis. Irisin is a newly discovered myokine that is secreted by skeletal muscle and adipose tissue. Serum Irisin was reported to be decreased in type 2 diabetes mellitus (T2DM) and/or osteoporosis patients, and it is correlated with bone mineral density (BMD) of neck bone, but its role in postmenopausal T2DM with osteoporosis remains largely unknown. Methods: Postmenopausal T2DM patients with or without osteoporosis were recruited, and 50 agematched healthy postmenopausal women were employed as healthy control. C57BL/6J mice were intraperitoneally injected with 65 mg/kg Streptozotocin (STZ) daily for consecutive 5 days to induce diabetes, and 1 mg/kg recombinant Irisin protein was injected into diabetic mice through the tail vein once a week for 4 months. Results: Compared to that of healthy control, serum Irisin levels and BMD in L1–L4 lumbar spine, femoral neck, total hip, and Wards were decreased in postmenopausal T2DM patients and further decreased in T2DM patients with osteoporosis. Moreover, serum Irisin levels were also correlated with BMD in the above body parts in T2DM patients. Furthermore, recombinant Irisin protein improved diabetic osteoporosis and inflammation in STZ-induced diabetic mice with osteoporosis. Conclusion: Serum Irisin levels in postmenopausal T2DM patients with osteoporosis were significantly decreased, which may be related to the decreased BMD and the occurrence of osteoporosis in postmenopausal T2DM patients. The combined measurement of serum Irisin levels and BMD in patients with T2DM in the early stage has a certain effect on the diagnosis and treatment of osteoporosis.