UniProt release 2015_04
Published April 1, 2015
Of CAT tails and protein translation by-products
Correct translation of mRNA into functional proteins is an essential cellular process. Defects in translation not only deprive cells of proteins needed for almost any task, but also produce by-products that can negatively impact these tasks and be toxic. Therefore translational garbage has to be removed.
One source of errors is defective ribosomes that stop during translation and hence produce incomplete polypeptide chains. All organisms have evolved mechanisms to manage translation arrest. In eukaryotes, ribosome stalling induces dissociation of the small 40S subunit and recruitment of the ‘ribosome quality control complex’ (RQC) to the large 60S subunit. RQC mediates the ubiquitination and degradation of the incompletely synthesized polypeptide chains.
Over the past few years, the mode of action of RQC has begun to be elucidated. The molecular components of RQC include listerin, an E3 ubiquitin ligase encoded by RKR1 in yeast and LTN1 in mammals, the AAA adenosine triphosphatase CDC48/VCP/p97 and ubiquitin-binding cofactors, as well as 2 proteins of unknown function. Listerin mediates the ubiquitination of the stalled polypeptide and subsequent recruitment of CDC48/VCP/p97 to the complex. The ATPase may provide the mechanical force to allow extraction of the nascent chain and its delivery to the proteasome for degradation.
Three recent studies have addressed the function of one of the uncharacterized proteins of the complex, called RQC2 in yeast and NEMF in mammals. In mammals, NEMF/RQC2 is responsible for the selective recognition of stalled 60S subunit. It does so by making multiple simultaneous contacts with 60S and peptidyl-tRNA to sense nascent chain occupancy. NEMF/RQC2 is also important for the stable association of listerin with the complex. Work in yeast not only corroborates these findings, but it reveals another unexpected function for NEMF/RQC2. NEMF/RQC2 recruits alanine- and threonine-charged tRNAs to the ribosomal A site and directs the elongation of stalled nascent chains independently of mRNA or 40S subunits, leading to non-templated C-terminal Ala and Thr extensions, aptly named CAT tails. The exact function of CAT tails is still under investigation, but they seem to induce an HSF1-dependent heat shock response in yeast through a mechanism that is yet to be determined. The heat shock response may help cells to buffer against malformed proteins. Alternatively, the extension at the C-terminus may serve to test the functional integrity of large ribosomal subunits, so that the cell can detect and dispose of defective large subunits that induce stalling.
mRNA-independent polypeptide biosynthesis has already been described in microorganisms. Classical examples of such peptides are peptide antibiotics, including actinomycin, bacitracin, colistin, and polymyxin B. In addition, in Staphylococcus aureus, pentaglycines acting as cross-linkers in the cell wall peptidoglycan are synthesized in the absence of mRNA. Although still considered as a very marginal event, the assembly of amino acids without mRNA blueprint might be more widespread than previously anticipated.
Reducing redundancy in proteomes
The UniProt Knowledgebase (UniProtKB) has witnessed an exponential growth in the last few years with a two-fold increase in the number of entries in 2014. This follows the vastly increased submission of multiple genomes for the same or closely related organisms. This increase has been accompanied by a high level of redundancy in UniProtKB/TrEMBL and many sequences are over-represented in the database. This is especially true for bacterial species where different strains of the same species have been sequenced and submitted (e.g. 1,692 strains of Mycobacterium tuberculosis, corresponding to 5.97 million entries). To reduce this redundancy, we have developed a procedure to identify highly redundant proteomes within species groups using a combination of manual and automatic methods. We have applied this procedure to bacterial proteomes (which constituted 81% of UniProtKB/TrEMBL in release 2015_03) and sequences corresponding to redundant proteomes (47 million entries) have been removed from UniProtKB. These sequences are still available in the UniParc sequence archive dataset within UniProt. From now on, we will no longer create new UniProtKB/TrEMBL records for proteomes identified as redundant.
Protein sequences belonging to proteomes that are not identified as redundant remain in UniProtKB. All proteomes are searchable through the UniProt website’s Proteomes pages. Sequences corresponding to redundant proteomes are available for download from UniParc and you will also be directed to alternate non-redundant proteome(s) available for the same species. The history (i.e. previous versions) of redundant UniProtKB records is still available.
Changes to the controlled vocabulary of human diseases
- Amyotrophic lateral sclerosis 22, with or without frontotemporal dementia
- Ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus
- Burn-McKeown syndrome
- Cerebellofaciodental syndrome
- Charcot-Marie-Tooth disease 2S
- Chronic atrial and intestinal dysrhythmia
- Congenital heart defects, hamartomas of tongue, and polysyndactyly
- Epilepsy, progressive myoclonic 7
- Epileptic encephalopathy, early infantile, 28
- Filippi syndrome
- Focal segmental glomerulosclerosis 9
- Galloway-Mowat syndrome
- Lacrimal duct defect
- Leber congenital amaurosis 18
- Mental retardation, autosomal dominant 31
- Mental retardation, autosomal recessive 47
- Peroxisomal fatty acyl-CoA reductase 1 disorder
- Pituitary adenoma, growth hormone-secreting, 2.
- Polyglucosan body myopathy 2
- Ruijs-Aalfs syndrome
- Spinocerebellar ataxia, autosomal recessive, 18
- Syndactyly, mesoaxial synostotic, with phalangeal reduction
- Waisman syndrome
- Adult-onset vitelliform macular dystrophy -> Macular dystrophy, vitelliform, 3
- Adult polyglucosan body disease -> Polyglucosan body neuropathy, adult form
- Brain small vessel disease with hemorrhage -> Brain small vessel disease with or without ocular anomalies
- Ectodermal dysplasia, with ectrodactyly and macular dystrophy -> Ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome
- Growth hormone-secreting pituitary adenoma -> Pituitary adenoma, growth hormone-secreting, 1
- Hyperuricemia pulmonary hypertension renal failure and alkalosis -> Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis syndrome
- Microcephaly and chorioretinopathy with or without mental retardation, autosomal recessive -> Microcephaly and chorioretinopathy, autosomal recessive, 1
- Pallister-Hall syndrome 1 -> Pallister-Hall syndrome
- Pallister-Hall syndrome 2 -> Culler-Jones syndrome
- Patterned dystrophy of retinal pigment epithelium -> Macular dystrophy, patterned, 1
- Polyglucosan body myopathy, early-onset, with or without immunodeficiency -> Polyglucosan body myopathy 1 with or without immunodeficiency
- Transaldolase 1 deficiency -> Transaldolase deficiency
- Acid phosphatase deficiency
Changes to keywords
- Viral host range expansion by genetic inversion -> Viral receptor tropism switching
Retirement of UniProt Metagenomic and Environmental Sequences (UniMES)
The UniProt Metagenomic and Environmental Sequences (UniMES) database was developed as a repository for metagenomic and environmental data. UniProt has retired UniMES as there is now a resource at the EBI that is dedicated to serving metagenomic researchers. Henceforth, we recommend using the EBI Metagenomics portal instead. In addition to providing a repository of metagenomics sequence data, EBI Metagenomics allows you to view functional and taxonomic analyses and to submit your own samples for analysis.