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Protein

Programmed cell death protein 6

Gene

Pdcd6

Organism
Mus musculus (Mouse)
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 (PubMed:10744743, PubMed:11525164, PubMed:27541325). 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:10744743, PubMed:11525164, PubMed:27541325). Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes (PubMed:10744743, PubMed:11525164, PubMed:27541325). 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 (By similarity). 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 (By similarity). Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway (By similarity). Promotes localization and polymerization of TFG at endoplasmic reticulum exit site (By similarity). Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis (PubMed:8560270). May mediate Ca2+-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity (By similarity). Its role in apoptosis may however be indirect, as suggested by knockout experiments (PubMed:12024023). May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway (By similarity).By similarity1 Publication4 Publications
Isoform 2: Has a lower Ca2+ affinity than isoform 1 (PubMed:10744743).1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi36Calcium 1Combined sources1 Publication1
Metal bindingi38Calcium 1Combined sources1 Publication1
Metal bindingi40Calcium 1Combined sources1 Publication1
Metal bindingi42Calcium 1; via carbonyl oxygenCombined sources1 Publication1
Metal bindingi47Calcium 1Combined sources1 Publication1
Metal bindingi103Calcium 2Combined sources1 Publication1
Metal bindingi105Calcium 2Combined sources1 Publication1
Metal bindingi107Calcium 2Combined sources1 Publication1
Metal bindingi109Calcium 2; via carbonyl oxygenCombined sources1 Publication1
Metal bindingi114Calcium 2Combined sources1 Publication1
Metal bindingi169MagnesiumCombined sources1 Publication1
Metal bindingi171MagnesiumCombined sources1 Publication1
Metal bindingi173MagnesiumCombined sources1 Publication1
Metal bindingi175Magnesium; via carbonyl oxygenCombined sources1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Calcium bindingi36 – 4711 PublicationAdd BLAST12
Calcium bindingi73 – 842PROSITE-ProRule annotationAdd BLAST12
Calcium bindingi103 – 11431 PublicationAdd 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: MGI
  • magnesium ion binding Source: UniProtKB
  • protein anchor Source: MGI
  • protein dimerization activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

Keywordsi

Biological processAngiogenesis, Apoptosis
LigandCalcium, Magnesium, Metal-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Programmed cell death protein 6
Alternative name(s):
ALG-257
Apoptosis-linked gene 2 protein1 Publication
Short name:
ALG-21 Publication
PMP41
Gene namesi
Name:Pdcd6
Synonyms:Alg21 Publication
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:109283. Pdcd6.

Subcellular locationi

  • Endoplasmic reticulum membrane By similarity; Peripheral membrane protein By similarity
  • Cytoplasmic vesicleCOPII-coated vesicle membrane By similarity
  • Cytoplasm By similarity
  • Nucleus By similarity
  • Endosome By similarity

  • Note: Interaction with RBM22 induces relocalization from the cytoplasm to the nucleus. 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. In response to calcium increase, relocates from cytolasm to COPII vesicle coat. Localizes to endoplasmic reticulum exit site (ERES).By similarity

GO - Cellular componenti

Keywords - Cellular componenti

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

Pathology & Biotechi

Disruption phenotypei

No visible phenotype (PubMed:12024023). Mice develop normally and display no obvious immune defect (PubMed:12024023). T-cells retain susceptibility to apoptotic stimuli (PubMed:12024023).1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi169D → A: Abolishes magnesium and calcium-binding to the EF-hand 5 domain (EF5). 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000737302 – 191Programmed cell death protein 6Add BLAST190

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1

Keywords - PTMi

Acetylation

Proteomic databases

EPDiP12815.
MaxQBiP12815.
PaxDbiP12815.
PeptideAtlasiP12815.
PRIDEiP12815.

PTM databases

PhosphoSitePlusiP12815.

Expressioni

Gene expression databases

BgeeiENSMUSG00000021576.
CleanExiMM_PDCD6.
GenevisibleiP12815. MM.

Interactioni

Subunit structurei

Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1 (PubMed:10200558, PubMed:11525164, PubMed:27541325). Isoform 1 and isoform 2 self-associate; probably forming homodimers (By similarity). Interacts with CPNE4 (via VWFA domain) (PubMed:12522145). Interacts with PDCD6IP; the interaction is calcium-dependent (PubMed:10200558, PubMed:10744743, PubMed:11525164). Interacts with RBM22 (By similarity). Interacts with PLSCR4 (By similarity). Interacts with ANXA7 and TSG101 (By similarity). Interacts with DAPK1 (By similarity). Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A (By similarity). Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent (By similarity). Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent (By similarity). Interacts with MCOLN1; the interaction is calcium-dependent (By similarity). Interacts with KDR; the interaction is calcium-dependent (By similarity). Interacts with HEBP2; the interaction is calcium-dependent (By similarity). Interacts with TFG (By similarity). 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:10744743).By similarity6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

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

Protein-protein interaction databases

BioGridi202071. 6 interactors.
ELMiP12815.
IntActiP12815. 10 interactors.
MINTiMINT-217398.
STRINGi10090.ENSMUSP00000022060.

Structurei

Secondary structure

1191
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi25 – 35Combined sources11
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
Helixi180 – 190Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HQVX-ray2.30A1-191[»]
5JJGX-ray1.72A24-191[»]
ProteinModelPortaliP12815.
SMRiP12815.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP12815.

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. 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). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3).By similarity
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:11525164). 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:11525164). EF5 acts as a high-affinity magnesium-binding domain instead (PubMed:27541325). Magnesium, may affect dimerization (PubMed:27541325). EF5 may bind either calcium or magnesium depending on the context.Curated2 Publications

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0037. Eukaryota.
ENOG410YKQK. LUCA.
GeneTreeiENSGT00620000087734.
HOGENOMiHOG000231984.
HOVERGENiHBG004492.
InParanoidiP12815.
OMAiFLWNIFQ.
OrthoDBiEOG091G0ISY.
PhylomeDBiP12815.
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 (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P12815-1) [UniParc]FASTAAdd to basket
Also known as: ALG-2,5

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 GGGPGPAAGA ALPDQSFLWN VFQRVDKDRS GVISDNELQQ
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):21,867
Last modified:November 1, 1997 - v2
Checksum:i2704E984BF7F6F40
GO
Isoform 2 (identifier: P12815-2) [UniParc]FASTAAdd to basket
Also known as: ALG-2,1

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

Show »
Length:189
Mass (Da):21,663
Checksum:i725B3EF5FDA06A72
GO

Sequence cautioni

The sequence CAA33064 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_047715121 – 122Missing in isoform 2. Curated2

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U49112 mRNA. Translation: AAB38108.1.
AK008610 mRNA. Translation: BAB25775.1.
AK028223 mRNA. Translation: BAC25823.1.
AK150335 mRNA. Translation: BAE29477.1.
BC040079 mRNA. Translation: AAH40079.1.
X14938 mRNA. Translation: CAA33064.1. Different initiation.
CCDSiCCDS26642.1. [P12815-1]
RefSeqiNP_035181.1. NM_011051.3. [P12815-1]
XP_006517219.1. XM_006517156.1. [P12815-2]
UniGeneiMm.24254.

Genome annotation databases

EnsembliENSMUST00000022060; ENSMUSP00000022060; ENSMUSG00000021576. [P12815-1]
ENSMUST00000222759; ENSMUSP00000152458; ENSMUSG00000021576. [P12815-2]
GeneIDi18570.
KEGGimmu:18570.
UCSCiuc007rey.2. mouse. [P12815-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiPDCD6_MOUSE
AccessioniPrimary (citable) accession number: P12815
Secondary accession number(s): Q545I0, Q61145
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: November 1, 1997
Last modified: August 30, 2017
This is version 164 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references