Derlin-1 (DERL1)

The protein contains 251 amino acids for an estimated molecular weight of 28801 Da.

 

Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins. May act by forming a channel that allows the retrotranslocation of misfolded proteins into the cytosol where they are ubiquitinated and degraded by the proteasome. May mediate the interaction between VCP and the misfolded protein (PubMed:15215856). Also involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation (PubMed:26565908). By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).', '(Microbial infection) In case of infection by cytomegaloviruses, it plays a central role in the export from the ER and subsequent degradation of MHC class I heavy chains via its interaction with US11 viral protein, which recognizes and associates with MHC class I heavy chains. Also participates in the degradation process of misfolded cytomegalovirus US2 protein. (updated: May 23, 2018)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

This protein is predicted to be membranous by TOPCONS.

Topcons

Interpro domains
Total structural coverage: 75%
Model score: 17
MODL_MODELLER-9.18

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VariantDescription
dbSNP:rs2272722

The reference OMIM entry for this protein is 608813

Der1-like domain family, member 1; derl1
Degradation in endoplasmic reticulum 1, yeast, homolog of; der1
Derlin 1

CLONING

Lilley and Ploegh (2004) used an affinity purification approach to identify human cellular proteins that interact with wildtype but not mutant human cytomegalovirus-encoded glycoprotein US11. They identified the DERL1 gene, which encodes a small hydrophobic protein of 251 amino acids predicted to span the lipid bilayer 4 times, with both its amino and carboxy termini in the cytosol. The Der1 gene encodes an evolutionarily conserved protein, with homologs in all eukaryotes examined by Lilley and Ploegh (2004). Yeast Der1p is known to be a factor in the degradation of misfolded endoplasmic reticulum (ER) proteins. Mammals have 2 additional Der1-like domain-containing proteins homologous to DERL1, which Lilley and Ploegh (2004) called DERL2 (610304) and DERL3 (610305). DERL2 and DERL3 are about 70% identical and probably originated from a gene duplication event in mammals.

MAPPING

Gross (2014) mapped the DERL1 gene to chromosome 8q24.13 based on an alignment of the DERL1 sequence (GenBank GENBANK BC002457) with the genomic sequence (GRCh37).

GENE FUNCTION

Lilley and Ploegh (2004) demonstrated that Derlin-1 is a widely expressed protein, with strong signals obtained by immunoblotting from liver, spleen, pancreas, lung, thymus, and ovary. Despite the presence of Derlin-1 sequences in brain cDNA libraries, immunoreactivity was not detected in brain. Lilley and Ploegh (2004) identified Derlin-1 as an ER membrane protein essential for US11-mediated dislocation of the major histocompatibility complex (MHC) class I (see 142800) heavy chain from the ER to the cytosol, and showed that Derlin-1 mediates the degradation of 2 different type 1 membrane proteins, class I MHC heavy chain and US2. Ye et al. (2004) identified a p97-interacting membrane protein complex in mammalian ER that links the recognition of a misfolded protein in the ER lumen with its subsequent movement through the membrane by the cytosolic p97 ATPase (VCP; 601023). The central component of the complex, Derlin-1, was found to associate with different substrates as they move through the membrane. Inactivation of Derlin-1 in C. elegans caused ER stress. Ye et al. (2004) found that Derlin-1 interacts with US11, a virally-encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP (607918), a membrane protein that recruits the p97 ATPase and its cofactor, a complex consisting of UFD1 (601754) and NPL4 (606590). Ye et al. (2004) found that VIMP links Derlin-1 with the p97 ATPase complex and that Derlin-1/VIMP is involved in US11-induced retrotranslocation. Cystic fibrosis (219700) arises from misfolding and premature degradation of CFTR (602421) containing a deletion of phe508 (delF508; 602421.0001). Younger et al. (2006) identified an ER membrane-associated ubiquitin ligase complex containing the E3 RMA1 (RNF5; 602677), the E2 UBC6E (UBE2J1; 616175), and derlin-1 that cooperated with the cytosolic HSC70 (HSPA8; 600816)/CHIP (STUB1; 607207) E3 complex to triage CFTR and delFl508. Derlin-1 retained CFTR in the ER membrane and interacted with RMA1 and UBC6E to promote proteasomal degradation of CFTR. RMA1 could recognize folding defects in delF508 coincident with translation, whereas CHIP appeared to act posttranslationally. A folding defect in delF508 detected by RMA1 involved the inability of the second membrane-spanning domain of CFTR to productively interact with N-terminal domains. Younger ... More on the omim web site

Subscribe to this protein entry history

May 26, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

June 20, 2017: Protein entry updated
Automatic update: comparative model was added.

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 608813 was added.