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UniProt release 2018_07

Published July 18, 2018

Headline

Ubiquitin ligation: new insight into mechanistic diversity

Protein ubiquitination is a reversible post-translational modification that is crucial for many physiological processes, from cell survival and differentiation to innate and adaptive immunity. It can affect protein functions at many levels, marking them for degradation, as well as regulating their cellular location, activity and interactions. Most frequently ubiquitin is linked to the amine group of a lysine side chain via an isopeptide bond, but a growing number of non-canonical linkages has been reported in recent years that involves the N-terminal amine group, thiol groups of cysteine side chains, and also serine and threonine hydroxyl groups.

A cascade of enzymatic reactions catalyzes the process of protein ubiquitination. The first step consists of ATP-dependent ubiquitin activation by E1 enzymes. Activated ubiquitin is transferred onto E2-conjugating enzymes, producing a covalently linked intermediate (E2-Ub). The transfer of ubiquitin onto the target protein is mediated by E3 protein ligases, which ensure the specificity of the reaction. The whole process grows in complexity with each step. The human genome is thought to encode only 2 E1 enzymes, some 40 E2s and over 600 E3 ligases. E3 ligases can be grouped into 3 classes based on their domain structure and mode of action. E3s of the ‘really interesting new gene’ (RING) family recruit E2-Ub via their RING domain and then mediate direct transfer of ubiquitin to substrates. By contrast, HECT E3 ligases undergo a catalytic cysteine-dependent transthiolation reaction with E2-Ub, forming a covalent E3-Ub intermediate. Finally, RING-between-RING (RBR) E3 ligases have a canonical RING domain linked to an ancillary domain. This ancillary domain contains a catalytic cysteine that enables a hybrid RING-HECT mechanism.

In order to identify new E3 enzymes of HECT or RBR classes, Pao et al. established an activity based assay, in which a biotinylated probe exhibiting the properties of a HECT/RBR substrate acts as a ‘suicide’ substrate and covalently traps target E3s. The assay worked as expected, identifying most known HECT/RBR, but much to their surprise, the authors also isolated 33 RING E3s that lacked HECT or RBR ancillary domains. One of these, MYCBP2, an E3 ligase involved in axon guidance and synapse formation in the developing nervous system, was found to mediate ubiquitination of serines and threonines, but not on lysines, with a strong preference for threonine. The enzymatic mechanism was also found to be novel: MYCBP2 relays ubiquitin to the target threonine via thioester intermediates involving 2 essential cysteines, a mechanism termed the ‘RING-Cys-relay’ (RCR).

Although non-canonical ubiquitination has already been observed, this is the first report of the identification of an enzyme catalyzing this reaction and along with it, a novel E3 mechanism has been unraveled. The annotation in MYCBP2 entries has been updated with this new knowledge and is publicly available as of this release.

UniProtKB news

Cross-references to UniLectin

Cross-references have been added to the UniLectin database, a database of carbohydrate-binding proteins.

UniLectin is available at https://unilectin.eu.

The format of the explicit links is:

Resource abbreviationUniLectin
Resource identifierUniProtKB accession number

Example: P84801

Show all entries having a cross-reference to UniLectin.

Text format

Example: P84801

DR   UniLectin; P84801; -.

XML format

Example: P84801

<dbReference type="UniLectin" id="P84801"/>

RDF format

Example: P84801

uniprot:P84801
  rdfs:seeAlso <http://purl.uniprot.org/unilectin/P84801> .
<http://purl.uniprot.org/unilectin/P84801>
  rdf:type up:Resource ;
  up:database <http://purl.uniprot.org/database/UniLectin> .

Changes to the controlled vocabulary of human diseases

New diseases:

Changes in subcellular location controlled vocabulary

New subcellular locations:

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