Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation.

As effective ways to regulate protein levels, targeted protein degradation technologies have attracted great attention in recent years. Here, we established a novel integrin-facilitated lysosomal degradation (IFLD) strategy to degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders. By conjugation of a target protein-binding ligand with an integrin-recognition ligand, the resulting molecular degrader proved to be highly efficient to induce the internalization and subsequent degradation of extracellular or cell membrane proteins in an integrin- and lysosome-dependent manner. As demonstrated in the development of BMS-L1-RGD, which is an efficient programmed death-ligand 1 (PD-L1) degrader validated both in vitro and in vivo, the IFLD strategy expands the toolbox for regulation of secreted and membrane-associated proteins and thus has great potential to be applied in chemical biology and drug discovery.

TRIM59 guards ER proteostasis and prevents Bortezomib-mediated colorectal cancer (CRC) cells' killing.

The endoplasmic reticulum (ER) is a critical organelle that preserves the protein homeostasis of cells. Under various stress conditions, cells evolve a degree of capacity to maintain ER proteostasis, which is usually augmented in tumor cells, including colorectal cancer (CRC) cells, to bolster their survival and resistance to apoptosis. Bortezomib (BTZ) is a promising drug used in CRC treatment; however, its main limitation result from drug resistance. Here, we identified the role of tripartite motif-containing protein 59 (TRIM59)-a protein localized on the ER membrane- in the prevention of BTZ-mediated CRC killing. Depletion of TRIM59 is associated with the enhancement of ER stress and a remarkable increase in unfolded protein response (UPR) signaling. Besides, TRIM59 strengthens ER-associated degradation (ERAD) and alleviates the generation of ROS. Of note, TRIM59 knockdown synergizes with the anti-cancer effect of BTZ both in vitro and in vivo. Our findings revealed a role for TRIM59 in the ER by guarding ER proteostasis and represents a novel therapeutic target of CRC.

Interaction mechanism between cereal phenolic acids and gluten protein: protein structural changes and binding mode.

BACKGROUND: Phenolic acids are antioxidant nutrients in cereals and affect the quality of wheat products and the properties of gluten protein. Gallic acid (GA), caffeic acid (CA), syringic acid (SA), and p-coumaric acid (p-CA) were selected to study the interaction mechanism between cereal phenolic acids and gluten protein. RESULTS: The results showed that adding GA significantly (P < 0.05) decreased the content of free sulfhydryl in gluten proteins by 70-87.26% compared with the control group. The aggregates' behavior of gluten protein induced by adding the phenolic acids would produce oversized particles (>5000 nm). Adding the selected phenolic acids changed the hydrogen-bond linkage of protein secondary structure. Zeta potential values of gluten protein increased significantly (P < 0.05) by 14.41%, 26.49%, 30.77%, and 57.93% for CA, p-CA, GA, and SA respectively added at 0.03 g kg-1 . Moreover, the gluten protein surface hydrophobicity increased when the phenolic acids were added at 0.03 g kg-1 , displaying the effect of the phenolic acid on the hydrophobic interaction of protein. Molecular docking results showed that the selected phenolic acids could interact with glutenin and gliadin using hydrogen-bond formation, and SA had the strongest binding with glutenin and gliadin. CONCLUSION: The results demonstrated that the selected phenolic acids could interact with gluten protein via covalent cross-linking as well as by hydrogen bonding, thereby changing the structure of the gluten protein. This exploration is expected to provide theoretical support for the development and utilization of whole-grain foods. © 2022 Society of Chemical Industry.

Effect of hydrocolloids on gluten proteins, dough, and flour products: A review.

Hydrocolloids are among the most common components in the food industry, which are used for thickening, gel formation, emulsification, and stabilization. Previous studies have also found that hydrocolloids can affect the structures and properties of gluten proteins, dough, and flour products. In this review, hydrocolloids were separated into three categories: anionic, nonionic, and other hydrocolloids, and reviewed the effects of common hydrocolloids on gluten proteins, dough, and flour products. Hydrocolloids can affect the structures and properties of gluten proteins through gluten-hydrocolloids interaction, secondary structures, disulfide bonds, environment of aromatic amino acids, and chemical bonds. The properties of dough are affected by rheological, fermentation, and thermomechanical properties. Hydrocolloids are widely used in bread, Chinese steamed bread, noodles, yellow layer cake, and so on, which mainly affect their appearance, texture, and aging speed. This comprehensive review provides a scientific guide for the development and utilization of hydrocolloids and their applications in flour products, and provides a theoretical basis for improving the processing characteristics of products.