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UniProt release 2018_05

Published May 23, 2018

Headline

Selenium vs. Sulfur: and the winner is...

Selenium is a chemical element that, in trace amounts, is essential for cellular function in many, though not all, organisms from all kingdoms of life. Proteins incorporate selenium as selenocysteine (Sec), where selenium replaces the sulfur of cysteine, when an UGA stop codon is “recoded” by a Sec-tRNA and a selenocysteine insertion sequence (SECIS) within target mRNA. Sec is indispensable for mammalian life and deficiency in Sec-tRNA is embryonic-lethal (shortly after implantation) in mice, yet this process is complex, inefficient and energetically costly. Why then does Mother Nature continue to produce selenoproteins in spite of these drawbacks?

Recent work from Ingold et al. suggests that one reason may be the ability of selenium to protect cells from a specific form of oxidative stress leading to cell death. The authors focused on the phospholipid hydroperoxide glutathione peroxidase GPX4, an essential selenoprotein and the only one whose knockout phenotype mimics that of Sec-tRNA gene disruption. GPX4 catalyzes the reduction of toxic lipid hydroperoxides formed when ferrous iron is imported into cells in the presence of reactive oxygen species produced during aerobic metabolism. If left unchecked, lipid peroxides can spontaneously propagate, directly damaging membranes or generating other toxic products, leading to a specific form of cell death, called ferroptosis. Mice in which the active site of GPX4 (Sec-73) is replaced by cysteine (GPX4-Cys) develop normally, but experience fatal seizures 2-3 weeks after birth. This phenotype is due to the lack of parvalbumin-positive GABAergic interneurons, which are important regulators of cortical network excitability. Hence the presence of Sec is essential for specific developmental events, such as the maturation of a specific class of neurons. In adult mice, the conditional expression of the GPX4-Cys mutant did not show any peculiar phenotype.

Cys substitution greatly reduces GPX4 activity, although it does not abolish it. In the presence of increasing levels of H2O2, GPX4-Cys readily undergoes irreversible oxidation and the mutant GPX4-Cys cells become exquisitely sensitive to peroxide-induced ferroptosis. In conclusion, the critical advantage of selenolate-versus thiolate-based catalysis may lie in its resistance to overoxidation when cells increase their metabolic rates and mitochondrial H2O2 production.

Selenium was discovered in 1817, almost exactly 200 years ago, and it is quite exciting to celebrate this anniversary with a new discovery about its role in higher organisms. As of this release, the updated GPX4 entries are publicly available.

Changes to the controlled vocabulary of human diseases

New diseases:

Deleted diseases

  • Epidermolysis bullosa dystrophica, Hallopeau-Siemens type
  • Epidermolysis bullosa dystrophica, Pasini type

Changes to the controlled vocabulary for PTMs

New term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):

  • Pyruvic acid (Tyr)

UniRef news

GO annotation to UniRef90 and UniRef50 clusters (also in clusters with one member)

In release 2017_05, we announced the addition of Gene Ontology (GO) annotations for UniRef90 and UniRef50 clusters: In this first approach, GO terms were assigned to clusters with at least 2 members, and a GO term was added to a cluster when it was found in all UniProtKB members, or when it was a common ancestor of at least one GO term of each member.

As of this release, 2018_05, we also adding GO annotations to UniRef90 and UniRef50 singleton clusters, i.e. clusters that have only one member. These clusters inherit the GO terms of their single member.

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