O75340 (PDCD6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Programmed cell death protein 6

Alternative name(s):
Apoptosis-linked gene 2 protein
Probable calcium-binding protein ALG-2

Gene names

Name:	PDCD6
Synonyms:	ALG2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	191 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Calcium-binding protein required for T-cell receptor-, Fas-, and glucocorticoid-induced cell death. May mediate Ca2+-regulated signals along the death pathway By similarity. Calcium-dependent adapter necessary for the association between PDCD6IP and TSG101. Interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity. Ref.9 Ref.13
Subunit structure	Self-associates By similarity. Homodimer. Interacts with PEF1. Interacts with RBM22. Interacts with PLSCR4, ANXA7 and TSG101. Interacts with SEC31A, PDCD6IP, and the N-termini of ANXA11 and PLSCR3 in a calcium-dependent manner. Interacts with DAPK1. Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.15
Subcellular location	Nucleus membrane; Peripheral membrane protein. Endoplasmic reticulum membrane; Peripheral membrane protein. Nucleus. Note: Interaction with RBM22 induces relocalization from the cytoplasm to the nucleus. Ref.11
Sequence similarities	Contains 5 EF-hand domains.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Endoplasmic reticulum Membrane Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	Calcium
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	induction of apoptosis by extracellular signals Traceable author statement. Source: ProtInc response to calcium ion Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	endoplasmic reticulum membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nuclear membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	binding, bridging Inferred from mutant phenotype Ref.13. Source: UniProtKB calcium ion binding Inferred from sequence or structural similarity. Source: UniProtKB calcium-dependent protein binding Inferred from physical interaction Ref.12. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DAPK1	P53355	3	EBI-352915,EBI-358616
PDCD6IP	Q8WUM4	5	EBI-352915,EBI-310624
PLSCR3	Q9NRY6	9	EBI-352915,EBI-750734
SEC31A	O94979	6	EBI-352915,EBI-1767898

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 191

191

Programmed cell death protein 6

PRO_0000073729

Regions

Domain

23 – 58

36

EF-hand 1

Domain

59 – 89

31

EF-hand 2

Domain

90 – 125

36

EF-hand 3

Domain

126 – 161

36

EF-hand 4

Domain

162 – 191

30

EF-hand 5

Calcium binding

36 – 47

12

1

Calcium binding

73 – 84

12

2 Potential

Calcium binding

103 – 114

12

3

Calcium binding

169 – 181

13

4

Natural variations

Natural variant

123

1

G → C in a breast cancer sample; somatic mutation. Ref.16

VAR_035459

Experimental info

Mutagenesis

47

1

E → A: Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-114. Ref.11 Ref.12

Mutagenesis

57

1

W → A: Reduces the interaction with PDCD6IP and ANXA7. Ref.12

Mutagenesis

60

1

F → A: Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. Ref.12

Mutagenesis

91

1

Y → A: Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. Ref.12

Mutagenesis

95

1

W → A: Abolishes the interaction with PDCD6IP, ANXA7 and ANXA11. Ref.12

Mutagenesis

114

1

E → A: Loss of interaction with SEC31A and PLSCR3, and loss of localization to the endoplasmic reticulum; when associated with A-47. Ref.11 Ref.12

Mutagenesis

180

1

Y → A: Abolishes the interaction with PDCD6IP, TSG101, ANXA7 and ANXA11. Ref.12

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

191

Helix Strand Turn

Details...

Helix

26 – 35

10

Helix

45 – 51

7

Helix

62 – 72

11

Beta strand

74 – 76

3

Helix

82 – 85

4

Helix

89 – 102

14

Helix

112 – 119

8

Helix

128 – 138

11

Helix

148 – 152

5

Helix

156 – 168

13

Helix

180 – 188

9

Sequences

	Sequence		Length	Mass (Da)
	O75340 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: D0B5944CF3C696AD	FASTA	191	21,868
	10 20 30 40 50 60 MAAYSYRPGP GAGPGPAAGA ALPDQSFLWN VFQRVDKDRS GVISDTELQQ ALSNGTWTPF 70 80 90 100 110 120 NPVTVRSIIS MFDRENKAGV NFSEFTGVWK YITDWQNVFR TYDRDNSGMI DKNELKQALS 130 140 150 160 170 180 GFGYRLSDQF HDILIRKFDR QGRGQIAFDD FIQGCIVLQR LTDIFRRYDT DQDGWIQVSY 190 EQYLSMVFSI V

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	Ganjei J.K., D'Adamio L. Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Urcelay E., Ibarreta D., Parrilla R., Ayuso M.S. Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Liver.
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[4]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Ovary.
[6]	"Peflin and ALG-2, members of the penta-EF-hand protein family, form a heterodimer that dissociates in a Ca2+-dependent manner." Kitaura Y., Matsumoto S., Satoh H., Hitomi K., Maki M. J. Biol. Chem. 276:14053-14058(2001) [PubMed: 11278427] [Abstract] Cited for: INTERACTION WITH PEF1.
[7]	"Both ALG-2 and peflin, penta-EF-hand (PEF) proteins, are stabilized by dimerization through their fifth EF-hand regions." Kitaura Y., Satoh H., Takahashi H., Shibata H., Maki M. Arch. Biochem. Biophys. 399:12-18(2002) [PubMed: 11883899] [Abstract] Cited for: INTERACTION WITH PEF1.
[8]	"ALG-2 interacts with the amino-terminal domain of annexin XI in a Ca(2+)-dependent manner." Satoh H., Shibata H., Nakano Y., Kitaura Y., Maki M. Biochem. Biophys. Res. Commun. 291:1166-1172(2002) [PubMed: 11883939] [Abstract] Cited for: INTERACTION WITH ANXA11.
[9]	"Programmed cell death 6 (PDCD6) protein interacts with death-associated protein kinase 1 (DAPk1): additive effect on apoptosis via caspase-3 dependent pathway." Lee J.H., Rho S.B., Chun T. Biotechnol. Lett. 27:1011-1015(2005) [PubMed: 16132846] [Abstract] Cited for: FUNCTION, INTERACTION WITH DAPK1.
[10]	"Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22." Montaville P., Dai Y., Cheung C.Y., Giller K., Becker S., Michalak M., Webb S.E., Miller A.L., Krebs J. Biochim. Biophys. Acta 1763:1335-1343(2006) [PubMed: 17045351] [Abstract] Cited for: INTERACTION WITH RBM22.
[11]	"The Ca2+-binding protein ALG-2 is recruited to endoplasmic reticulum exit sites by Sec31A and stabilizes the localization of Sec31A." Yamasaki A., Tani K., Yamamoto A., Kitamura N., Komada M. Mol. Biol. Cell 17:4876-4887(2006) [PubMed: 16957052] [Abstract] Cited for: INTERACTION WITH SEC31A AND PDCD6IP, MUTAGENESIS OF GLU-47 AND GLU-114, SUBCELLULAR LOCATION.
[12]	"Identification of Alix-type and non-Alix-type ALG-2-binding sites in human phospholipid scramblase 3: differential binding to an alternatively spliced isoform and amino acid-substituted mutants." Shibata H., Suzuki H., Kakiuchi T., Inuzuka T., Yoshida H., Mizuno T., Maki M. J. Biol. Chem. 283:9623-9632(2008) [PubMed: 18256029] [Abstract] Cited for: INTERACTION WITH PLSCR3; PLSCR4; PDCD6IP; ANXA7; ANXA11; SEC31A AND TSG101, MUTAGENESIS OF GLU-47; TRP-57; PHE-60; TYR-91; TRP-95; GLU-114 AND TYR-180.
[13]	"Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor that bridges Alix and TSG101." Okumura M., Ichioka F., Kobayashi R., Suzuki H., Yoshida H., Shibata H., Maki M. Biochem. Biophys. Res. Commun. 386:237-241(2009) [PubMed: 19520058] [Abstract] Cited for: FUNCTION.
[14]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Structural basis for Ca2+ -dependent formation of ALG-2/Alix peptide complex: Ca2+/EF3-driven arginine switch mechanism." Suzuki H., Kawasaki M., Inuzuka T., Okumura M., Kakiuchi T., Shibata H., Wakatsuki S., Maki M. Structure 16:1562-1573(2008) [PubMed: 18940611] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 24-191 IN COMPLEXES WITH CALCIUM; ZINC AND PDCD6IP, SUBUNIT, INTERACTION WITH PDCD6IP.
[16]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] CYS-123.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF035606 mRNA. Translation: AAC27697.1.
U58773 mRNA. Translation: AAF14336.1.
AK315370 mRNA. Translation: BAG37763.1.
BT020072 mRNA. Translation: AAV38875.1.
BC012384 mRNA. Translation: AAH12384.1.
BC106706 mRNA. Translation: AAI06707.1.

IPI

IPI00025277.

RefSeq

NP_037364.1. NM_013232.3.

UniGene

Hs.50823.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2ZN8	X-ray	2.70	A	2-191	[»]
2ZN9	X-ray	2.40	A/B	20-191	[»]
2ZND	X-ray	1.70	A	20-191	[»]
2ZNE	X-ray	2.20	A/B	24-191	[»]
2ZRS	X-ray	3.10	A/B/C/D/E/F/G/H	24-191	[»]
2ZRT	X-ray	3.30	A/B/C/D/E/F/G/H	24-191	[»]
3AAJ	X-ray	2.40	A/B	24-191	[»]
3AAK	X-ray	2.70	A	20-191	[»]

ProteinModelPortal

O75340.

SMR

O75340. Positions 24-191.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33217N.

IntAct

O75340. 26 interactions.

MINT

MINT-5000341.

STRING

O75340.

PTM databases

PhosphoSite

O75340.

Proteomic databases

PRIDE

O75340.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264933; ENSP00000264933; ENSG00000249915.

GeneID

10016.

KEGG

hsa:10016.

UCSC

uc003jat.1. human.

Organism-specific databases

CTD

10016.

GeneCards

GC05P000258.

H-InvDB

HIX0004700.

HGNC

HGNC:8765. PDCD6.

MIM

601057. gene.

neXtProt

NX_O75340.

PharmGKB

PA33115.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04609.

HOVERGEN

HBG004492.

OMA

ISDNELQ.

OrthoDB

EOG4H464S.

PhylomeDB

O75340.

Gene expression databases

ArrayExpress

O75340.

Bgee

O75340.

CleanEx

HS_ALG2.
HS_PDCD6.

Genevestigator

O75340.

GermOnline

ENSG00000063438. Homo sapiens.

Family and domain databases

InterPro

IPR018248. EF-hand.
IPR011992. EF-hand-like_dom.
IPR018247. EF_Hand_1_Ca_BS.
IPR018249. EF_HAND_2.
IPR002048. EF_hand_Ca-bd.
[Graphical view]

Gene3D

G3DSA:1.10.238.10. EF-Hand_type. 1 hit.

Pfam

PF00036. efhand. 1 hit.
[Graphical view]

SMART

SM00054. EFh. 5 hits.
[Graphical view]

PROSITE

PS00018. EF_HAND_1. 2 hits.
PS50222. EF_HAND_2. 3 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

37841.

SOURCE

Search...

Entry information

Entry name

PDCD6_HUMAN

Accession

Primary (citable) accession number: O75340
Secondary accession number(s): B2RD16, Q5TZS0

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 11, 2001
Last sequence update:	November 1, 1998
Last modified:	December 14, 2011
This is version 109 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.