Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

Programmed cell death protein 6

Gene

PDCD6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 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).By similarity9 Publications
Isoform 2: Has a lower Ca2+ affinity than isoform 1 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi36Calcium 14 Publications1
Metal bindingi38Calcium 14 Publications1
Metal bindingi40Calcium 14 Publications1
Metal bindingi42Calcium 1; via carbonyl oxygen4 Publications1
Metal bindingi47Calcium 14 Publications1
Metal bindingi103Calcium 24 Publications1
Metal bindingi105Calcium 24 Publications1
Metal bindingi107Calcium 24 Publications1
Metal bindingi109Calcium 2; via carbonyl oxygen4 Publications1
Metal bindingi114Calcium 24 Publications1
Metal bindingi169MagnesiumBy similarity1
Metal bindingi171MagnesiumBy similarity1
Metal bindingi173MagnesiumBy similarity1
Metal bindingi175Magnesium; via carbonyl oxygenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi36 – 4714 PublicationsAdd BLAST12
Calcium bindingi73 – 842PROSITE-ProRule annotationAdd BLAST12
Calcium bindingi103 – 11434 PublicationsAdd BLAST12

GO - Molecular functioni

  • binding, bridging Source: UniProtKB
  • calcium-dependent cysteine-type endopeptidase activity Source: GO_Central
  • calcium-dependent protein binding Source: UniProtKB
  • calcium ion binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • magnesium ion binding Source: UniProtKB
  • protein anchor Source: UniProtKB
  • protein dimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: Ensembl
  • angiogenesis Source: UniProtKB-KW
  • apoptotic signaling pathway Source: ProtInc
  • cellular response to heat Source: UniProtKB
  • COPII vesicle coating Source: UniProtKB
  • ER to Golgi vesicle-mediated transport Source: UniProtKB
  • intracellular protein transport Source: UniProtKB
  • negative regulation of protein kinase B signaling Source: UniProtKB
  • negative regulation of TOR signaling Source: UniProtKB
  • negative regulation of vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
  • neural crest cell development Source: UniProtKB
  • neural crest formation Source: UniProtKB
  • positive regulation of angiogenesis Source: UniProtKB
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • positive regulation of endothelial cell migration Source: UniProtKB
  • positive regulation of endothelial cell proliferation Source: UniProtKB
  • positive regulation of protein monoubiquitination Source: UniProtKB
  • response to calcium ion Source: UniProtKB
  • vascular endothelial growth factor receptor-2 signaling pathway Source: UniProtKB

Keywordsi

Biological processAngiogenesis, Apoptosis
LigandCalcium, Magnesium, Metal-binding

Protein family/group databases

TCDBi3.A.5.9.1. the general secretory pathway (sec) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Programmed cell death protein 6
Alternative name(s):
Apoptosis-linked gene 2 protein homologBy similarity
Short name:
ALG-2By similarity
Gene namesi
Name:PDCD6
Synonyms:ALG2By similarity
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

EuPathDBiHostDB:ENSG00000249915.7.
HGNCiHGNC:8765. PDCD6.

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Cytoplasmic vesicle, Endoplasmic reticulum, Endosome, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi47E → A: Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-114. 3 Publications1
Mutagenesisi52L → A: Stronly impaired interaction with SEC31A. Slightly reduced interaction with PDCD6IP. 1 Publication1
Mutagenesisi53S → G: Slightly reduced interaction with SEC31A. Does not affect interaction with PDCD6IP. 1 Publication1
Mutagenesisi57W → A: Does not affect interaction with SEC31A. Reduces the interaction with HEBP2, PDCD6IP and ANXA7. 3 Publications1
Mutagenesisi60F → A: Abolishes the interaction with SEC31A, PDCD6IP, ANXA7 and ANXA11. 2 Publications1
Mutagenesisi85F → A: Stronly impaired interaction with SEC31A and TFG. Does not affect interaction with PDCD6IP. 2 Publications1
Mutagenesisi89W → A: Does not affect interaction with SEC31A. Does not affect interaction with PDCD6IP. 1 Publication1
Mutagenesisi91Y → A: Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. 1 Publication1
Mutagenesisi92I → A: Does not affect interaction with SEC31A. Does not affect interaction with PDCD6IP. 1 Publication1
Mutagenesisi95W → A: Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. 1 Publication1
Mutagenesisi114E → A: Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-47. 2 Publications1
Mutagenesisi122F → A: Increases interaction with PDCD6IP and ANXA7. Impairs interaction with ANXA11. Augments stauroporine-induced cell death. 1 Publication1
Mutagenesisi122F → G: Increases interaction with PDCD6IP. Impairs interaction with ANXA11. 1 Publication1
Mutagenesisi122F → S: Increases interaction with PDCD6IP. Impairs interaction with ANAX7 and ANXA11. 1 Publication1
Mutagenesisi122F → W: Impairs interaction with ANXA11. 1 Publication1
Mutagenesisi148F → S: Slightly reduced interaction with SEC31A. Does not affect interaction with PDCD6IP. 1 Publication1
Mutagenesisi180Y → A: Abolishes the interaction with PDCD6IP, TSG101, ANXA7 and ANXA11. Does not affect interaction with TFG and SEC31A. 2 Publications1

Organism-specific databases

DisGeNETi10016.
OpenTargetsiENSG00000249915.
PharmGKBiPA33115.

Polymorphism and mutation databases

BioMutaiPDCD6.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00000737292 – 191Programmed cell death protein 6Add BLAST190

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1

Keywords - PTMi

Acetylation

Proteomic databases

EPDiO75340.
MaxQBiO75340.
PaxDbiO75340.
PeptideAtlasiO75340.
PRIDEiO75340.
TopDownProteomicsiO75340-1. [O75340-1]

PTM databases

iPTMnetiO75340.
PhosphoSitePlusiO75340.

Expressioni

Gene expression databases

BgeeiENSG00000249915.
CleanExiHS_ALG2.
HS_PDCD6.
ExpressionAtlasiO75340. baseline and differential.
GenevisibleiO75340. HS.

Organism-specific databases

HPAiHPA047221.

Interactioni

Subunit structurei

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:27716508, PubMed:25667979). 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).By similarity16 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • calcium-dependent protein binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • protein anchor Source: UniProtKB
  • protein dimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi115333. 104 interactors.
CORUMiO75340.
DIPiDIP-33217N.
ELMiO75340.
IntActiO75340. 63 interactors.
MINTiMINT-5000341.
STRINGi9606.ENSP00000264933.

Structurei

Secondary structure

1191
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi26 – 35Combined sources10
Beta strandi36 – 40Combined sources5
Beta strandi41 – 43Combined sources3
Helixi45 – 51Combined sources7
Beta strandi55 – 58Combined sources4
Helixi62 – 72Combined sources11
Beta strandi74 – 80Combined sources7
Helixi82 – 102Combined sources21
Beta strandi107 – 110Combined sources4
Helixi112 – 121Combined sources10
Helixi128 – 138Combined sources11
Beta strandi143 – 147Combined sources5
Helixi148 – 168Combined sources21
Beta strandi172 – 174Combined sources3
Helixi180 – 188Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2ZN8X-ray2.70A2-191[»]
2ZN9X-ray2.40A/B20-191[»]
2ZNDX-ray1.70A20-191[»]
2ZNEX-ray2.20A/B24-191[»]
2ZRSX-ray3.10A/B/C/D/E/F/G/H24-191[»]
2ZRTX-ray3.30A/B/C/D/E/F/G/H24-191[»]
3AAJX-ray2.40A/B24-191[»]
3AAKX-ray2.70A20-191[»]
3WXAX-ray2.36A/B20-191[»]
5GQQX-ray2.20C/D24-191[»]
ProteinModelPortaliO75340.
SMRiO75340.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO75340.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini23 – 58EF-hand 1PROSITE-ProRule annotationAdd BLAST36
Domaini59 – 89EF-hand 2PROSITE-ProRule annotationAdd BLAST31
Domaini90 – 125EF-hand 3PROSITE-ProRule annotationAdd BLAST36
Domaini126 – 161EF-hand 4PROSITE-ProRule annotationAdd BLAST36
Domaini162 – 191EF-hand 5PROSITE-ProRule annotationAdd BLAST30

Domaini

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).2 Publications
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).By similarity2 Publications

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0037. Eukaryota.
ENOG410YKQK. LUCA.
GeneTreeiENSGT00620000087734.
HOGENOMiHOG000231984.
HOVERGENiHBG004492.
InParanoidiO75340.
OMAiFLWNIFQ.
OrthoDBiEOG091G0ISY.
PhylomeDBiO75340.
TreeFamiTF314682.

Family and domain databases

InterProiView protein in InterPro
IPR011992. EF-hand-dom_pair.
IPR018247. EF_Hand_1_Ca_BS.
IPR002048. EF_hand_dom.
PfamiView protein in Pfam
PF13202. EF-hand_5. 1 hit.
PF13499. EF-hand_7. 1 hit.
SMARTiView protein in SMART
SM00054. EFh. 5 hits.
SUPFAMiSSF47473. SSF47473. 1 hit.
PROSITEiView protein in PROSITE
PS00018. EF_HAND_1. 2 hits.
PS50222. EF_HAND_2. 3 hits.

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O75340-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MAAYSYRPGP GAGPGPAAGA ALPDQSFLWN VFQRVDKDRS GVISDTELQQ
60 70 80 90 100
ALSNGTWTPF NPVTVRSIIS MFDRENKAGV NFSEFTGVWK YITDWQNVFR
110 120 130 140 150
TYDRDNSGMI DKNELKQALS GFGYRLSDQF HDILIRKFDR QGRGQIAFDD
160 170 180 190
FIQGCIVLQR LTDIFRRYDT DQDGWIQVSY EQYLSMVFSI V
Length:191
Mass (Da):21,868
Last modified:November 1, 1998 - v1
Checksum:iD0B5944CF3C696AD
GO
Isoform 2 (identifier: O75340-2) [UniParc]FASTAAdd to basket
Also known as: ALG-2(delta)GF122

The sequence of this isoform differs from the canonical sequence as follows:
     121-122: Missing.

Show »
Length:189
Mass (Da):21,664
Checksum:i8F93724C044DD93A
GO
Isoform 3 (identifier: O75340-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     70-191: Missing.

Note: No experimental confirmation available.
Show »
Length:69
Mass (Da):7,349
Checksum:i8410709B76C52B47
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_035459123G → C in a breast cancer sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04554270 – 191Missing in isoform 3. 1 PublicationAdd BLAST122
Alternative sequenceiVSP_045113121 – 122Missing in isoform 2. 1 Publication2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF035606 mRNA. Translation: AAC27697.1.
U58773 mRNA. Translation: AAF14336.1.
AK315370 mRNA. Translation: BAG37763.1.
BT020072 mRNA. Translation: AAV38875.1.
AC010442 Genomic DNA. No translation available.
AC021087 Genomic DNA. No translation available.
AC118458 Genomic DNA. No translation available.
CH471235 Genomic DNA. Translation: EAW50991.1.
BC012384 mRNA. Translation: AAH12384.1.
BC106706 mRNA. Translation: AAI06707.1.
BC110291 mRNA. Translation: AAI10292.1.
CB991882 mRNA. No translation available.
CCDSiCCDS3854.1. [O75340-1]
CCDS58940.1. [O75340-2]
CCDS58941.1. [O75340-3]
RefSeqiNP_001254485.1. NM_001267556.1. [O75340-2]
NP_001254486.1. NM_001267557.1.
NP_001254487.1. NM_001267558.1.
NP_001254488.1. NM_001267559.1. [O75340-3]
NP_037364.1. NM_013232.3. [O75340-1]
UniGeneiHs.50823.

Genome annotation databases

EnsembliENST00000264933; ENSP00000264933; ENSG00000249915. [O75340-1]
ENST00000505221; ENSP00000422085; ENSG00000249915. [O75340-3]
ENST00000507528; ENSP00000423815; ENSG00000249915. [O75340-2]
GeneIDi10016.
KEGGihsa:10016.
UCSCiuc003jat.1. human. [O75340-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiPDCD6_HUMAN
AccessioniPrimary (citable) accession number: O75340
Secondary accession number(s): B2RD16
, E7ESR3, Q2YDC2, Q5TZS0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: November 1, 1998
Last modified: September 27, 2017
This is version 169 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references