Ribosome Rescue Ribosomes stall when they reach the end of defective messenger RNAs (mRNAs). In bacteria, the most-studied ribosomal rescue pathway involves a ribonucleoprotein complex comprising tmRNA (which acts as both transfer RNA and mRNA) and the protein SmpB. In an alternative pathway, some Gram-negative bacteria contain proteins that achieve tmRNA-independent rescue. Now, Neubauer et al. (p. 1366 ) present the structure of the Thermus thermophilus ribosome bound to a fragment of tmRNA, SmpB, and elongation factor Tu, and Gagnon et al. (p. 1370 ) report the structure of the T. thermophilus ribosome in complex with an initiator tRNA, a short mRNA fragment, and the rescue factor YaeJ. Though the two rescue systems are very different, both involve a protein tail that binds in the mRNA channel. This orients the rescue apparatus to facilitate switching translation to a different message in the tmRNA system or hydrolysis of peptidyl tRNA by YaeJ.
Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis.. ) is a reactive byproduct of mitochondrial respiration and fatty acid oxidation that can damage critical cellular components. To protect against such damage, cells express antioxidant enzymes such as copper-zinc superoxide dismutase (SOD1) 5 (1), catalase (2), and glutathione peroxidase (3) that together act to convert superoxide to molecular oxygen and water using redox-active metal cofactors. SOD1 comprises between 0.1 and 2.0% of the detergent-soluble protein in spinal cord and brain (4, 5), and this abundance presumably protects against the plentiful superoxide generated by these metabolically active (respiring) tissues. However, expression of SOD1 variants can be harmful if the molecule functions abnormally as demonstrated by dominantly inherited mutations in the human SOD1 gene that give rise to familial forms of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) (6, 7).Seminal studies in transgenic mice have established that pathogenic SOD1 proteins elicit motor neuron dysfunction through the acquisition of a deleterious property and not a loss of enzymatic function (8 -10). Proteinaceous inclusions enriched in SOD1 are observed in cell culture model systems, ALS-SOD1 transgenic mice, and in familial ALS patients, suggesting that SOD1-linked ALS pathology may be related to protein misfolding or aggregation (for reviews, see Refs. 11-13). However, the molecular mechanisms underlying SOD1 toxicity to motor neurons remain unknown, and it remains to be clarified whether the observed inclusions are causal or symptomatic of motor neuron dysfunction.Since the discovery of the SOD1-ALS link nearly 15 years ago, the pathogenic human SOD1 variant in which Arg is substituted for Gly at position 85 (G85R) has been frequently studied. When expressed in transgenic mice, G85R SOD1 causes rapidly progressive motor neuron degeneration while remaining at low levels in the soluble fraction of spinal cord extracts (14 -16). Visible SOD1-containing inclusions first become apparent in astrocytes with the o...
Mutations in human copper-zinc superoxide dismutase (SOD1) cause an inherited form of amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease, motor neuron disease). Insoluble forms of mutant SOD1 accumulate in neural tissues of human ALS patients and in spinal cords of transgenic mice expressing these polypeptides, suggesting that SOD1-linked ALS is a protein misfolding disorder. Understanding the molecular basis for how the pathogenic mutations give rise to SOD1 folding intermediates, which may themselves be toxic, is therefore of keen interest. A critical step on the SOD1 folding pathway occurs when the copper chaperone for SOD1 (CCS) modifies the nascent SOD1 polypeptide by inserting the catalytic copper cofactor and oxidizing its intrasubunit disulfide bond. Recent studies reveal that pathogenic SOD1 proteins coming from cultured cells and from the spinal cords of transgenic mice tend to be metal-deficient and/or lacking the disulfide bond, raising the possibility that the disease-causing mutations may enhance levels of SOD1-folding intermediates by preventing or hindering CCS-mediated SOD1 maturation. This mini-review explores this hypothesis by highlighting the structural and biophysical properties of the pathogenic SOD1 mutants in the context of what is currently known about CCS structure and action. Other hypotheses as to the nature of toxicity inherent in pathogenic SOD1 proteins are not covered.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.