O75340 · PDCD6_HUMAN
- ProteinProgrammed cell death protein 6
- GenePDCD6
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids191 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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 a 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 Ca2+-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (PubMed:16132846).
Its role in apoptosis may however be indirect, as suggested by knockout experiments (By similarity).
May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (PubMed:21893193).
In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution (PubMed:27784779).
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 a 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 Ca2+-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (PubMed:16132846).
Its role in apoptosis may however be indirect, as suggested by knockout experiments (By similarity).
May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (PubMed:21893193).
In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution (PubMed:27784779).
Isoform 2
Has a lower Ca2+ affinity than isoform 1 (By similarity).
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 36 | Ca2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 38 | Ca2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 40 | Ca2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 42 | Ca2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: V | ||||||
Binding site | 47 | Ca2+ 1 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 103 | Ca2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 105 | Ca2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 107 | Ca2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 109 | Ca2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: M | ||||||
Binding site | 114 | Ca2+ 2 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 169 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 171 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 173 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 175 | Mg2+ (UniProtKB | ChEBI) | ||||
Sequence: W |
GO annotations
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameProgrammed cell death protein 6
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO75340
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Peripheral membrane protein
Note: Interaction with RBM22 induces relocalization from the cytoplasm to the nucleus (PubMed:17045351).
Translocated from the cytoplasm to the nucleus after heat shock cell treatment. Accumulates in cytoplasmic vesicle-like organelles after heat shock treatment, which may represent stress granules (PubMed:21122810).
In response to calcium increase, relocates from cytoplasm to COPII vesicle coat (PubMed:27716508).
Localizes to endoplasmic reticulum exit site (ERES) (PubMed:27813252).
Translocated from the cytoplasm to the nucleus after heat shock cell treatment. Accumulates in cytoplasmic vesicle-like organelles after heat shock treatment, which may represent stress granules (PubMed:21122810).
In response to calcium increase, relocates from cytoplasm to COPII vesicle coat (PubMed:27716508).
Localizes to endoplasmic reticulum exit site (ERES) (PubMed:27813252).
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 47 | Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-114. | ||||
Sequence: E → A | ||||||
Mutagenesis | 52 | Strongly impaired interaction with SEC31A. Slightly reduced interaction with PDCD6IP. | ||||
Sequence: L → A | ||||||
Mutagenesis | 53 | Slightly reduced interaction with SEC31A. Does not affect interaction with PDCD6IP. | ||||
Sequence: S → G | ||||||
Mutagenesis | 57 | Does not affect interaction with SEC31A. Reduces the interaction with HEBP2, PDCD6IP and ANXA7. | ||||
Sequence: W → A | ||||||
Mutagenesis | 60 | Abolishes the interaction with SEC31A, PDCD6IP, ANXA7 and ANXA11. | ||||
Sequence: F → A | ||||||
Mutagenesis | 85 | Strongly impaired interaction with SEC31A and TFG. Does not affect interaction with PDCD6IP. | ||||
Sequence: F → A | ||||||
Mutagenesis | 89 | Does not affect interaction with SEC31A. Does not affect interaction with PDCD6IP. | ||||
Sequence: W → A | ||||||
Mutagenesis | 91 | Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. | ||||
Sequence: Y → A | ||||||
Mutagenesis | 92 | Does not affect interaction with SEC31A. Does not affect interaction with PDCD6IP. | ||||
Sequence: I → A | ||||||
Mutagenesis | 95 | Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. | ||||
Sequence: W → A | ||||||
Mutagenesis | 114 | Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-47. | ||||
Sequence: E → A | ||||||
Mutagenesis | 122 | Increases interaction with PDCD6IP and ANXA7. Impairs interaction with ANXA11. Augments stauroporine-induced cell death. | ||||
Sequence: F → A | ||||||
Mutagenesis | 122 | Increases interaction with PDCD6IP. Impairs interaction with ANXA11. | ||||
Sequence: F → G | ||||||
Mutagenesis | 122 | Increases interaction with PDCD6IP. Impairs interaction with ANAX7 and ANXA11. | ||||
Sequence: F → S | ||||||
Mutagenesis | 122 | Impairs interaction with ANXA11. | ||||
Sequence: F → W | ||||||
Natural variant | VAR_035459 | 123 | in a breast cancer sample; somatic mutation | |||
Sequence: G → C | ||||||
Mutagenesis | 148 | Slightly reduced interaction with SEC31A. Does not affect interaction with PDCD6IP. | ||||
Sequence: F → S | ||||||
Mutagenesis | 180 | Abolishes the interaction with PDCD6IP, TSG101, ANXA7 and ANXA11. Does not affect interaction with TFG and SEC31A. | ||||
Sequence: Y → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 218 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, modified residue, chain, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Modified residue | 2 | UniProt | N-acetylalanine | ||||
Sequence: A | |||||||
Chain | PRO_0000073729 | 2-191 | UniProt | Programmed cell death protein 6 | |||
Sequence: AAYSYRPGPGAGPGPAAGAALPDQSFLWNVFQRVDKDRSGVISDTELQQALSNGTWTPFNPVTVRSIISMFDRENKAGVNFSEFTGVWKYITDWQNVFRTYDRDNSGMIDKNELKQALSGFGYRLSDQFHDILIRKFDRQGRGQIAFDDFIQGCIVLQRLTDIFRRYDTDQDGWIQVSYEQYLSMVFSIV | |||||||
Modified residue (large scale data) | 5 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 107 | PRIDE | Phosphoserine | ||||
Sequence: S |
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1 (PubMed:11278427, PubMed:11883899, PubMed:27784779).
Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain) (By similarity).
Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:16957052, PubMed:18256029, PubMed:18940611, PubMed:20691033, PubMed:25667979).
Interacts with RBM22 (PubMed:17045351).
Interacts with PLSCR4 (PubMed:18256029).
Interacts with ANXA7 and TSG101 (PubMed:18256029, PubMed:20691033).
Interacts with DAPK1 (PubMed:16132846).
Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (PubMed:16957052, PubMed:18256029, PubMed:25667979, PubMed:27716508).
Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (PubMed:11883939, PubMed:18256029, PubMed:18940611).
Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (PubMed:18256029).
Interacts with MCOLN1; the interaction is calcium-dependent (PubMed:19864416).
Interacts with KDR; the interaction is calcium-dependent (PubMed:21893193).
Interacts with HEBP2; the interaction is calcium-dependent (PubMed:27784779).
Interacts with TFG (PubMed:27813252).
Isoform 1: Interacts with SHISA5, leading to stabilize it (PubMed:17889823).
Isoform 2: Does not interact with SHISA5 (PubMed:17889823).
Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (PubMed:18256029, PubMed:20691033).
Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain) (By similarity).
Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:16957052, PubMed:18256029, PubMed:18940611, PubMed:20691033, PubMed:25667979).
Interacts with RBM22 (PubMed:17045351).
Interacts with PLSCR4 (PubMed:18256029).
Interacts with ANXA7 and TSG101 (PubMed:18256029, PubMed:20691033).
Interacts with DAPK1 (PubMed:16132846).
Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (PubMed:16957052, PubMed:18256029, PubMed:25667979, PubMed:27716508).
Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (PubMed:11883939, PubMed:18256029, PubMed:18940611).
Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (PubMed:18256029).
Interacts with MCOLN1; the interaction is calcium-dependent (PubMed:19864416).
Interacts with KDR; the interaction is calcium-dependent (PubMed:21893193).
Interacts with HEBP2; the interaction is calcium-dependent (PubMed:27784779).
Interacts with TFG (PubMed:27813252).
Isoform 1: Interacts with SHISA5, leading to stabilize it (PubMed:17889823).
Isoform 2: Does not interact with SHISA5 (PubMed:17889823).
Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11 (PubMed:18256029, PubMed:20691033).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | O75340 | ANXA11 P50995 | 5 | EBI-352915, EBI-715243 | |
BINARY | O75340 | ANXA11 Q5T0G8 | 3 | EBI-352915, EBI-10245225 | |
BINARY | O75340 | BAG4 O95429 | 3 | EBI-352915, EBI-2949658 | |
BINARY | O75340 | DAPK1 P53355 | 3 | EBI-352915, EBI-358616 | |
BINARY | O75340 | DCTN2 Q13561 | 4 | EBI-352915, EBI-715074 | |
BINARY | O75340 | HEBP2 Q9Y5Z4 | 9 | EBI-352915, EBI-741593 | |
BINARY | O75340 | KDR P35968 | 4 | EBI-352915, EBI-1005487 | |
BINARY | O75340 | PDCD6 O75340 | 4 | EBI-352915, EBI-352915 | |
BINARY | O75340 | PDCD6IP Q8WUM4 | 13 | EBI-352915, EBI-310624 | |
BINARY | O75340 | PEF1 Q9UBV8 | 12 | EBI-352915, EBI-724639 | |
BINARY | O75340 | PLSCR3 Q9NRY6 | 9 | EBI-352915, EBI-750734 | |
BINARY | O75340 | PRR19 A6NJB7-2 | 3 | EBI-352915, EBI-11998870 | |
BINARY | O75340 | PTPN23 Q9H3S7 | 3 | EBI-352915, EBI-724478 | |
BINARY | O75340 | SEC31A O94979 | 7 | EBI-352915, EBI-1767898 | |
BINARY | O75340 | VPS37C A5D8V6 | 6 | EBI-352915, EBI-2559305 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 23-58 | EF-hand 1 | ||||
Sequence: PDQSFLWNVFQRVDKDRSGVISDTELQQALSNGTWT | ||||||
Domain | 59-89 | EF-hand 2 | ||||
Sequence: PFNPVTVRSIISMFDRENKAGVNFSEFTGVW | ||||||
Domain | 90-125 | EF-hand 3 | ||||
Sequence: KYITDWQNVFRTYDRDNSGMIDKNELKQALSGFGYR | ||||||
Domain | 126-161 | EF-hand 4 | ||||
Sequence: LSDQFHDILIRKFDRQGRGQIAFDDFIQGCIVLQRL | ||||||
Domain | 162-191 | EF-hand 5 | ||||
Sequence: TDIFRRYDTDQDGWIQVSYEQYLSMVFSIV |
Domain
Interacts with different set of proteins thanks to 3 different hydrophobic pockets (PubMed:20691033, PubMed:25667979).
Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr-180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2) (PubMed:20691033).
Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3) (PubMed:25667979).
Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr-180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2) (PubMed:20691033).
Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3) (PubMed:25667979).
EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium-binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity (PubMed:18940611, PubMed:20691033).
A one-residue insertion in the EF5-binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand (PubMed:18940611, PubMed:20691033).
EF5 acts as a high-affinity magnesium-binding domain instead (By similarity).
Magnesium, may affect dimerization (By similarity).
EF5 may bind either calcium or magnesium depending on the context (By similarity).
A one-residue insertion in the EF5-binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand (PubMed:18940611, PubMed:20691033).
EF5 acts as a high-affinity magnesium-binding domain instead (By similarity).
Magnesium, may affect dimerization (By similarity).
EF5 may bind either calcium or magnesium depending on the context (By similarity).
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 3 isoforms produced by Alternative splicing.
O75340-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length191
- Mass (Da)21,868
- Last updated1998-11-01 v1
- ChecksumD0B5944CF3C696AD
O75340-2
- Name2
- SynonymsALG-2(delta)GF122
- Differences from canonical
- 121-122: Missing
O75340-3
- Name3
- Differences from canonical
- 70-191: Missing
Computationally mapped potential isoform sequences
There are 5 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
D6RA21 | D6RA21_HUMAN | PDCD6 | 39 | ||
H0Y9X3 | H0Y9X3_HUMAN | PDCD6 | 104 | ||
Q86W51 | Q86W51_HUMAN | PDCD6 | 55 | ||
A0A024QZ42 | A0A024QZ42_HUMAN | PDCD6 | 121 | ||
A0A087WZ38 | A0A087WZ38_HUMAN | PDCD6 | 123 |
Features
Showing features for alternative sequence.
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF035606 EMBL· GenBank· DDBJ | AAC27697.1 EMBL· GenBank· DDBJ | mRNA | ||
U58773 EMBL· GenBank· DDBJ | AAF14336.1 EMBL· GenBank· DDBJ | mRNA | ||
AK315370 EMBL· GenBank· DDBJ | BAG37763.1 EMBL· GenBank· DDBJ | mRNA | ||
BT020072 EMBL· GenBank· DDBJ | AAV38875.1 EMBL· GenBank· DDBJ | mRNA | ||
AC010442 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AC021087 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AC118458 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH471235 EMBL· GenBank· DDBJ | EAW50991.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC012384 EMBL· GenBank· DDBJ | AAH12384.1 EMBL· GenBank· DDBJ | mRNA | ||
BC106706 EMBL· GenBank· DDBJ | AAI06707.1 EMBL· GenBank· DDBJ | mRNA | ||
BC110291 EMBL· GenBank· DDBJ | AAI10292.1 EMBL· GenBank· DDBJ | mRNA | ||
CB991882 EMBL· GenBank· DDBJ | - | mRNA | No translation available. |