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751.
The glucagon receptor antagonist BI-32169, recently isolated from Streptomyces sp., was described as a bicyclic peptide, although its primary structure comprises conserved elements of class I and class II lasso peptides. Tandem mass spectrometric and nuclear magnetic resonance spectroscopic studies revealed that BI-32169 is a lasso-structured peptide constituting the new class III of lasso peptides. The determined lasso fold opens new avenues to improve the promising biological activity of BI-32169. 相似文献
752.
753.
《Journal of molecular biology》2023,435(12):168140
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence is increasing with age. A wealth of genetic evidence indicates that the endo-lysosomal system is a major pathway driving PD pathogenesis with a growing number of genes encoding endo-lysosomal proteins identified as risk factors for PD, making it a promising target for therapeutic intervention. However, detailed knowledge and understanding of the molecular mechanisms linking these genes to the disease are available for only a handful of them (e.g. LRRK2, GBA1, VPS35). Taking on the challenge of studying poorly characterized genes and proteins can be daunting, due to the limited availability of tools and knowledge from previous literature. This review aims at providing a valuable source of molecular and cellular insights into the biology of lesser-studied PD-linked endo-lysosomal genes, to help and encourage researchers in filling the knowledge gap around these less popular genetic players. Specific endo-lysosomal pathways discussed range from endocytosis, sorting, and vesicular trafficking to the regulation of membrane lipids of these membrane-bound organelles and the specific enzymatic activities they contain. We also provide perspectives on future challenges that the community needs to tackle and propose approaches to move forward in our understanding of these poorly studied endo-lysosomal genes. This will help harness their potential in designing innovative and efficient treatments to ultimately re-establish neuronal homeostasis in PD but also other diseases involving endo-lysosomal dysfunction. 相似文献
754.
Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys208–Cys241 disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys208/Cys241-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys208/Cys241 loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity. 相似文献
755.
Xinmiao Fu 《Archives of biochemistry and biophysics》2009,485(1):1-169
Protein disulfide isomerase (PDI) and its homologs are catalysts of the formation of disulfide bonds in secretory proteins, and they also serve as molecular chaperones. In the present study, we investigated the redox-mediated regulation of the structures and functions of human pancreas-specific PDI homolog (PDIp). We found that formation of an inter-subunit disulfide bond in the recombinant human PDIp can alter not only its structure, but also its functions. PDIp exists predominantly as monomer under reducing conditions, but the dimeric form is significantly increased following the removal of the reducing agent, due to the formation of an inter-subunit disulfide bond. The oxidized PDIp (with an inter-subunit disulfide bond) appears to expose more hydrophobic patches and is more sensitive to protease digestion compared to the reduced form. Along with these structural changes, the oxidized PDIp also exhibits an enhanced chaperone activity. The formation of the inter-subunit disulfide bond in PDIp is mainly contributed by its non-active cysteine residue (cysteine-4), which is only present in human and primate PDIp, but not in rodent PDIp. In addition, we observed that the formation of the inter-subunit disulfide bond in PDIp is redox-dependent and is favored under oxidizing conditions, and that PDIp can function as a chaperone to form stable complexes with various non-native cellular proteins, particularly under oxidizing conditions. In light of these observations, it is concluded that the structures and functions of human PDIp are redox-regulated through formation of an inter-subunit disulfide bond between two cysteine-4 residues. 相似文献
756.
John Ong Junzhe Zhao Alexander W. Justin Athina E. Markaki 《Biotechnology and bioengineering》2019,116(12):3457-3468
Albumin, the most abundant plasma protein in mammals, is a versatile and easily obtainable biomaterial. It is pH and temperature responsive, dissolvable in high concentrations and gels readily in defined conditions. This versatility, together with its inexpensiveness and biocompatibility, makes albumin an attractive biomaterial for biomedical research and therapeutics. So far, clinical research in albumin has centered mainly on its use as a carrier molecule or nanoparticle to improve drug pharmacokinetics and delivery to target sites. In contrast, research in albumin-based hydrogels is less established albeit growing in interest over recent years. In this minireview, we report current literature and critically discuss the synthesis, mechanical properties, biological effects and uses, biodegradability and cost of albumin hydrogels as a xeno-free, customizable, and transplantable construct for tissue engineering and regenerative medicine. 相似文献
757.
BackgroundPreviously, we had reported that α-chymotrypsin–catalyzed polymerization of l-cysteine ethyl ester in a frozen buffer provided poly-l-cysteine (PLCys) in good yield, of which degree of polymerization had been determined to be 6–11. Almost all of SH groups in PLCys were in free forms. Such a multi-thiol peptide may cross-link proteins through thiol/disulfide (SH/SS) exchange reactions, considering the knowledge that other synthetic multi-thiol additives changes properties of protein materials.MethodsThis study explored the capability of PLCys to cross-link proteins using lysozyme as a model protein which has four disulfide bonds but no free SH group. The protein was incubated with PLCys at neutral pH and at below 70 °C to avoid PLCys-independent, β-elimination-mediated cross-linkings. Protein polymerization was analyzed by SDS-PAGE and SEC. PLCys peptides involved in the protein polymer, which were released by reduction with dithiothreitol, were analyzed by RP-HPLC.ConclusionsAddition of urea and thermal treatment at 60 °C caused PLCys-induced lysozyme polymerization. Compared with free cysteine, a higher level of PLCys was required for the polymerization probably due to its low water solubility. RP-HPLC analyses suggested that PLCys played a role in the protein polymerization as a cross-linker.General significanceEnzymatically synthesized PLCys shows promise as a peptidic cross-linker for the production of protein polymers with novel physiochemical properties and functionalities. 相似文献
758.
Crude lipase from Rhizopus sp. was moderately stable against heat treatment at 45 °C. However, after incubation for 1 h at 25 °C with Streptoverticillium transglutaminase (MTG), the half-life of crude lipase in the heat treatment was increased more than 10-fold compared to that of untreated one. The result can be ascribed by the MTGase-mediated crosslinking of contaminating proteins that affect the apparent thermostability of lipase in the crude sample. 相似文献
759.
《Molecular cell》2023,83(11):1936-1952.e7
760.
The positions of the disulfide bonds of huwentoxin-I, a neurotoxin from the spiderSelenocosmia huwena, have been determined. The existence of three disulfide bonds in the native toxin was demonstrated by mass spectroscopy and the lack of reactivity with a thiol reagent. The assignment procedure involved a combination of tryptic digestion of the native toxin and sequence analysis of both intact andin situ S-carboxymethylated toxin.In situ carboxymethylation is shown to be a useful procedure in sequencing of cysteine- and cystine-containing peptides. Sequence analysis of the intact, cross-linked toxin indicated that no amino acid phenylthiohydantoin (PTH) derivative is seen for the first half-cystine in a cross-linked pair, but that the PTH of dehydroalanine, which can be detected at 313 nm, is seen at the position of the second half-cystine. By sequencing disulfide cross-linked tryptic fragments, the three disulfide linkages in huwentoxin-I could be assigned as Cys2-Cys17, Cys9-Cys22, and Cys16-Cys29. 相似文献