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UniProt release 2015_01

Published January 7, 2015

Headline

Thalidomide, the pharmacological version of yin and yang

In the 1950s, the German company Chemie Gruenenthal brought a new drug to the market, thalidomide. It was primarily used as a sedative, but as it also had anti-emetic properties, it soon became popular to alleviate “morning sickness” in pregnant women. About 10,000 children were born to women taking thalidomide. They exhibited severe malformations, affecting limbs, ears, heart and other internal organs and only 50% survived. By the early sixties, the teratogenic effect of thalidomide had been established and its use discontinued. However, scientists’ interest in this molecule never stopped. In 1965, thalidomide was shown to have immunomodulatory and anti-inflammatory properties in patients with erythema nodosum leprosum, an inflammatory complication of leprosy. More recently, thalidomide was proved to be efficient against several hematological cancers, including multiple myeloma, inhibiting cancer cell proliferation, modulating the immune system and the tumor microenvironment.

In 60 years, observations on thalidomide effects have accumulated, but its mode of action is still not fully elucidated. Nevertheless, some major steps have been accomplished to achieve this aim. A major breakthrough came in 2010 when thalidomide’s primary target, a protein called cereblon (CRBN), was identified. CRBN is a component of a ubiquitin E3 complex, called CRL4. This complex is made of at least 4 proteins, CUL4, DDB1, RBX1 and CRBN. Each protein has its specific function. CUL4 provides a scaffold for assembly of RBX1 and DDB1, RBX1 is the docking site for the activated E2 protein, and DDB1 recruits substrate-specificity receptors, such as CRBN, that form the substrate-presenting side of the CRL4 complex. The recently published CRL4 3D structure revealed that the ligase arm of CUL4 is quite mobile, establishing a ubiquitination zone. As it is a promiscuous enzyme, any lysine crossing this zone may be a target.

How does thalidomide affect CRBN activity within the CRL4 complex? In the presence of thalidomide, 2 transcription factors, IKZF1 and IKZF3, are recognized by CRBN and targeted for destruction by the proteasome. Neither of these proteins are substrates in the absence of the drug. Under normal conditions, IKZF1 and IKZF3 regulate B-and T-cell development. IKZF1 suppresses the expression of IL2 in T-cells and stimulates the expression of IRF4. This observation sheds light upon the immunomodulatory effects of thalidomide. What about endogenous CRBN substrates? Until recently, none were known. Last July, Fisher et al. published the results of their search for proteins whose ubiquitination by CRL4/CRBN was inhibited by thalidomide (or thalidomide derivatives) and identified MEIS2, a homeodomain-containing protein. MEIS2 has been involved in some aspects of normal human development. In bats, differential MEIS2 expression has been observed during limb development. A failure in limb development is a very striking feature of “thalidomide babies”. Hence MEIS2 may be a candidate for some aspects of thalidomide-induced teratogenicity.

Based on 3D structure analysis of the CRL4 complex, a model has been proposed in which thalidomide binds to CRBN at the canonical substrate-binding site. This interferes with the binding of endogenous CRBN substrates, impairs their ubiquitination and subsequent destruction, and results in their up-regulation. Conversely, the presence of thalidomide modifies the CRBN surface, creating a new binding site for neo-substrates, leading to their down-regulation.

As of this release, the updated versions of CRBN, DDB1, CUL4B, RBX1 entries are available in UniProtKB/Swiss-Prot.

UniProtKB news

Cross-references to UniProt Proteomes

For several years now, UniProt has been providing ‘proteome’ sets of proteins thought to be expressed by organisms whose genomes have been completely sequenced. In the past, these sets were based on the taxonomy of the organisms, but as more and more genomes of the same organism are being sequenced, we have recently introduced unique proteome identifiers to distinguish individual proteomes. These proteomes can be queried and downloaded from the new Proteomes section of the UniProt website. UniProtKB entries that are part of a proteome now have a cross-reference to their proteome and, where known, we also indicate the name of the component that encodes the respective protein.

UniProt Proteomes are available at http://www.uniprot.org/proteomes/.

The format of the explicit links is:

Resource abbreviation Proteomes
Resource identifier Proteome identifier.
Optional information 1 Component name.

Example: P78363

Text format

Example: P78363

DR   Proteomes; UP000005640; Chromosome 1.

XML format

Example: P78363

<dbReference type="Proteomes" id="UP000005640">
  <property type="component" value="Chromosome 1"/>
</dbReference>

RDF format

In the RDF format, we have introduced a new property proteome to represent a proteomes resource. The component is indicated by a relative URI reference.

Example: P78363

uniprot:P78363
  up:proteome <http://purl.uniprot.org/proteomes/UP000005640#Chromosome%201> .

Cross-references to DEPOD

Cross-references have been added to DEPOD, the human DEPhOsphorylation Database.

DEPOD is available at http://www.koehn.embl.de/depod/.

The format of the explicit links is:

Resource abbreviation DEPOD
Resource identifier UniProtKB accession number.

Example: Q99502

Show all entries having a cross-reference to DEPOD.

Text format

Example: Q99502

DR   DEPOD; Q99502; -.

XML format

Example: Q99502

<dbReference type="DEPOD" id="Q99502"/>

Cross-references to MoonProt

Cross-references have been added to MoonProt, a manually curated database containing information about the known moonlighting proteins.

MoonProt is available at http://www.moonlightingproteins.org/.

The format of the explicit links is:

Resource abbreviation MoonProt
Resource identifier UniProtKB accession number.

Example: P31230

Show all entries having a cross-reference to MoonProt.

Text format

Example: P31230

DR   MoonProt; P31230; -.

XML format

Example: P31230

<dbReference type="MoonProt" id="P31230"/>

Changes to the controlled vocabulary of human diseases

New diseases: