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Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.
Skelet Muscle
October 2024
Center for Cardiometabolic Science, Louisville, KY, USA.
Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways.
View Article and Find Full Text PDFHow the double-ring ClpAP protease motor grips the substrate to unfold and degrade stable proteins.
J Biol Chem
November 2024
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. Electronic address:
Loops in the axial channels of ClpAP and other AAA+ proteases bind a short peptide degron connected by a linker to the N- or C-terminal residue of a native protein to initiate degradation. ATP hydrolysis then powers pore-loop movements that translocate these segments through the channel until a native domain is pulled against the narrow channel entrance, creating an unfolding force. Substrate unfolding is thought to depend on strong contacts between pore loops and a subset of amino acids in the unstructured sequence directly preceding the folded domain.
View Article and Find Full Text PDFGastrodin Improves the Activity of the Ubiquitin-Proteasome System and the Autophagy-Lysosome Pathway to Degrade Mutant Huntingtin.
Int J Mol Sci
July 2024
Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Article Synopsis
- Gastrodin (GAS), derived from the traditional Chinese herb "Tianma," has been studied for its potential effects on Huntington's disease (HD), specifically on the mutant huntingtin protein (mHtt) in PC12 cells.
- Research showed that while GAS did not affect cell survival at certain concentrations, it improved the degradation of mHtt by enhancing the ubiquitin-proteasome system (UPS) and activating the autophagy-lysosome pathway (ALP), thus reducing neuronal damage.
- In vivo, high-dose oral administration of GAS (100 mg/kg) in transgenic mice improved grip strength and decreased mHtt aggregates, suggesting a therapeutic potential for GAS in HD which requires further dose
Slippery sequences stall the 26S proteasome at multiple points along the translocation pathway.
Protein Sci
June 2024
Department of Chemistry, Villanova University, Villanova, Pennsylvania, USA.
In eukaryotes, the ubiquitin-proteasome system is responsible for intracellular protein degradation. Proteins tagged with ubiquitin are recognized by ubiquitin receptors on the 19S regulatory particle (RP) of the 26S proteasome, unfolded, routed through the translocation channel of the RP, and are then degraded in the 20S core particle (CP). Aromatic paddles on the pore-1 loops of the RP's Rpt subunits grip the substrate and pull folded domains into the channel, thereby unfolding them.
View Article and Find Full Text PDFPotyviral Helper-Component Protease: Multifaced Functions and Interactions with Host Proteins.
Plants (Basel)
April 2024
Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, 128 43 Prague, Czech Republic.
The best-characterized functional motifs of the potyviral Helper-Component protease (HC-Pro) responding for aphid transmission, RNA silencing suppression, movement, symptom development, and replication are gathered in this review. The potential cellular protein targets of plant virus proteases remain largely unknown despite their multifunctionality. The HC-Pro catalytic domain, as a cysteine protease, autoproteolytically cleaves the potyviral polyproteins in the sequence motif YXVG/G and is not expected to act on host targets; however, 146 plant proteins in the clade containing this motif were searched in the UniProtKB database and are discussed.
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