Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

UniProt release 2014_08

Published September 3, 2014

Headline

Ubiquitin caught at its own game

Ubiquitination is a widely used post-translational modification (PTM) in eukaryotic cells. It is involved in a plethora of cellular activities ranging from removal of misfolded and unwanted proteins to signaling in innate immunity, from transcriptional regulation to membrane trafficking. Ubiquitination is the covalent attachment of the small 76-residue protein ubiquitin onto a target protein, most often via an isopeptide bond between the amino group of a lysine side chain and ubiquitin C-terminus. This process occurs in several steps: an ubiquitin-activation step catalyzed by E1 enzymes, an ubiquitin-conjugation step catalyzed by E2 enzymes, and a step ensuring the target specificity involving E3 ligases. Many different types of ubiquitination exist, monoubiquitination, multi(mono)ubiquitination and polyubiquitination, each type conveying a different signal. Polyubiquitination occurs via further ubiquitination of a single lysine residue on the substrate protein. Ubiquitin contains 7 ubiquitin lysines; each can serve as an acceptor for further elongation and each defines a distinct fate for the modified protein. The classic example is the Lys-48-linked chain which targets the protein bearing it to degradation via the proteasome.

An additional step of complexity has been unveiled in 3 recent publications: Ubiquitin was discovered to be itself subjected to another PTM, namely phosphorylation, which confers on it the ability to activate the E3 ubiquitin-protein ligase Parkin (PARK2).

Parkin and the PINK1 kinase are involved in the signaling pathway leading to mitophagy, a specialized program which eliminates damaged mitochondria and hence maintains health. Indeed, defects in any of these proteins cause early-onset Parkinson disease.

Under normal conditions, PINK1 is imported into mitochondria, where it is processed and rapidly degraded. When mitochondria lose membrane potential or amass unfolded proteins, PINK1 accumulates on the outer membrane where it recruits cytosolic Parkin and activates its latent E3 activity. As a result, mitochondrial outer membrane proteins are ubiquitinated and the defective organelle is targeted for destruction.

It is in the Parkin activation step that phosphorylated ubiquitin comes into play. PINK1 directly phosphorylates ubiquitin at Ser-65. Of note, Parkin itself contains a ubiquitin-like domain that is also phosphorylated by PINK1 at Ser-65. All three publications agree that phosphorylated ubiquitin is involved in the PINK1/PARK2 pathway. Nevertheless Koyano and colleagues found that both ubiquitin and Parkin Ser-65 phosphorylations are needed for full Parkin activation, whereas Kane et al. observed Parkin activation with phospho-ubiquitin alone. While phospho-ubiquitin can be used by Parkin as a substrate for ubiquitination, its Parkin-binding and -activating abilities seem to be separated from its role as a substrate.

As of this release, human Parkin, PINK1 and ubiquitin entries have been updated accordingly and annotations have been transferred to orthologous entries based on sequence similarity. Proteins known to undergo ubiquitination can be retrieved with the keyword Ubl conjugation and proteins involved in the ubiquitination pathway, such as E1, E2 or E3 enzymes, with the keyword Ubl conjugation pathway.

UniProtKB news

New variant types in homo_sapiens_variation.txt.gz on the UniProt FTP site

UniProt would like to announce the addition of two variant types, stop lost and stop gained, to the set of protein altering variants from the 1000 Genomes Project available in the homo_sapiens_variation.txt.gz file. Stop lost and stop gained variants have been selected as the first structural variants to be added to the UniProt variant catalogue because they are two of the most commonly occurring variant types. UniProt expects to add further structural variant types and somatic variants to the available variant types and to include additional species. This file, along with the humsavar.txt file, can now be found in the new dedicated variants directory in the UniProt FTP site. We very much welcome the feedback of the community on our efforts.

Changes to the controlled vocabulary of human diseases

New diseases:

Modified diseases:

Deleted diseases:

  • Ichthyosis, autosomal recessive, with hypotrichosis
  • Loeys-Dietz syndrome 2A
  • Loeys-Dietz syndrome 2B

Changes to the controlled vocabulary for PTMs

New terms for the feature key ‘Cross-link’ (‘CROSSLNK’ in the flat file):

  • Isoaspartyl glycine isopeptide (Asn-Gly)
  • Isoaspartyl glycine isopeptide (Asp-Gly)

Deleted terms:

  • Aspartyl isopeptide (Asn)
  • Aspartyl isopeptide (Asp)

Changes to keywords

Modified keyword:

Website news

The UniProt website is changing

We would like to introduce you to the new UniProt website! We have been working on this site behind the scenes for a while and we’re glad it’s finally time to share it with you.

We redesigned the UniProt website following a user centered design process, involving over 250 users worldwide with varied research backgrounds and use cases. User centered design is a design approach that is grounded in the requirements and expectations of users. They are included at every stage of the process, from gathering requirements to testing the end product.

Some highlights of the changes and improvements:

  • A new homepage and advanced search functionality
  • A new results page interface with easy to use filters
  • A basket to store your favorite proteins and build up your own set
  • New protein entry page content classification and navigation bar
  • New tool output interfaces (e.g. BLAST results)
  • New ‘Proteomes’ pages for full protein sets from completely sequenced organisms

Contextual help is available on the site as well as UniProt help videos from the UniProt YouTube channel. We look forward to feedback from the scientific community to help improve the site further.