Programmed cell death protein 6 (PDCD6)
The protein contains 191 amino acids for an estimated molecular weight of 21868 Da.
Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes (PubMed:20691033, PubMed:25667979). Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (PubMed:19520058). Together with PEF1, acts as calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats (PubMed:27716508). In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification (PubMed:27716508). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (PubMed:19864416). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (PubMed:27813252). Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis (By similarity). May mediate Ca(2+)-regulated signals alo (updated: Nov. 22, 2017)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- 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.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
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.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
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.
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| Variant | Description |
|---|---|
| a breast cancer sample; somatic mutation |
Biological Process
Activation of cysteine-type endopeptidase activity involved in apoptotic process
Angiogenesis
Apoptotic signaling pathway
Cellular response to heat
COPII vesicle coating
Endoplasmic reticulum to Golgi vesicle-mediated transport
Intracellular protein transport
Negative regulation of protein kinase B signaling
Negative regulation of TOR signaling
Negative regulation of vascular endothelial growth factor receptor signaling pathway
Neural crest cell development
Neural crest formation
Positive regulation of angiogenesis
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
Positive regulation of endothelial cell migration
Positive regulation of endothelial cell proliferation
Positive regulation of protein monoubiquitination
Proteolysis
Response to calcium ion
Vascular endothelial growth factor receptor-2 signaling pathway
Cellular Component
COPII vesicle coat
Cul3-RING ubiquitin ligase complex
Cytoplasm
Cytoplasmic vesicle
Cytosol
Endoplasmic reticulum
Endoplasmic reticulum exit site
Endoplasmic reticulum membrane
Endosome
Extracellular exosome
Golgi membrane
Nuclear membrane
Nucleoplasm
Nucleus
Molecular Function
Calcium ion binding
Calcium-dependent cysteine-type endopeptidase activity
Calcium-dependent protein binding
Identical protein binding
Magnesium ion binding
Molecular adaptor activity
Protein dimerization activity
Protein homodimerization activity
Protein-macromolecule adaptor activity
Protein-membrane adaptor activity
Ubiquitin ligase-substrate adaptor activity
The reference OMIM entry for this protein is 601057
Programmed cell death 6; pdcd6
Apoptosis-linked gene 2; alg2
CLONING
The normal development of multicellular organisms is dependent on the removal of 'unwanted' cells by a genetically controlled process termed programmed cell death (PCD) that is typically mediated by apoptosis. Dysregulation of this process contributes to or is suspected of contributing to the pathogenesis of several diseases, including neurodegenerative disorders (see 253300), cancer (see 151430), autoimmune disease (see FAS; 134637), congenital malformations (see 185900), and immunodeficiency. Vito et al. (1996) designed a method to select genes involved in apoptosis, using as a model PCD induced in a mouse T-cell hybridoma by T-cell receptor cross-linking. The selection system, which they named 'death trap,' is based on the assumption that a transfected cDNA library constructed in the mammalian expression vector pLTP should protect some recipient cells from death. Such inhibition may depend on inactivation of apoptotic genes by either antisense RNA or dominant-negative mutants or on overexpression of proteins with antiapoptotic activity. Using this system, they isolated 6 cDNA clones, designated apoptosis-linked genes (Alg1 to Alg6), that were able to inhibit PCR-induced cell death in a transient transfection assay. Vito et al. (1996) found that a 435-bp mouse Alg2 cDNA identified a single 1.3-kb transcript in mouse T-cell hybridoma cells and in all adult mouse tissues analyzed. The thymus and liver showed the most expression, whereas the testis and skeletal muscles showed the least. The full-length Alg2 cDNA has an open reading frame predicted to encode a protein of 191 amino acids.GENE FUNCTION
Vito et al. (1996) showed that mouse Alg2 is a Ca(2+)-binding protein required for T-cell receptor-, Fas-, and glucocorticoid-induced cell death. Using immunoblot analysis, Jung et al. (2001) showed that ALG2 is expressed as a 22-kD protein before FAS activation and thereafter as a 19-kD protein, probably due to N-terminal cleavage. Confocal microscopy and immunoprecipitation analysis demonstrated that ALG2 translocates from the cytoplasmic membrane to the cytosol during FAS-induced apoptosis and then dissociates from FAS after activation. Yeast 2-hybrid and GST pull-down analyses confirmed that ALG2 interacts with FAS. Kitaura et al. (2001) found that ALG2 coimmunoprecipitated with peflin (PEF1; 610033) from Jurkat human T cells and from transfected HEK293 cells. Peflin dissociated from ALG2 in the presence of Ca(2+), and the N-terminal hydrophobic domain of peflin was not essential for heterodimerization. Peflin and ALG2 colocalized in the cytoplasm, but ALG2 was also detected in nuclei, as revealed by immunofluorescence staining and subcellular fractionation. Peflin was recovered in the cytosolic fraction in the absence of Ca(2+) and in the membrane/cytoskeletal fraction in the presence of Ca(2+). Kitaura et al. (2001) concluded that peflin may modulate the function of ALG2 in Ca(2+) signaling.ANIMAL MODEL
Jang et al. (2002) generated viable and fertile mice deficient in Alg2 by gene targeting. The mice were developmentally and immunologically normal. Analysis of apoptotic responses demonstrated that the Alg2 deficiency resulted in no block of apoptosis induced by TCR, FAS, or dexamethasone signals. Jang et al. (2002) concluded that ALG2 is physiologically dispensable in these signaling pathways and that other functionally redundant proteins might exist in mammalian cells. ... More on the omim web site
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
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for PDCD6
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601057 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed