Q61823 (PDCD4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Programmed cell death protein 4

Alternative name(s):
Protein MA-3
Topoisomerase-inhibitor suppressed protein

Gene names

Name:	Pdcd4
Synonyms:	Ma3, Tis

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	469 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Inhibits translation initiation and cap-dependent translation. May excert its function by hindering the interaction between EIF4A1 and EIF4G. Inhibits the helicase activity of EIF4A. Modulates the activation of JUN kinase. Down-regulates the expression of MAP4K1, thus inhibiting events important in driving invasion, namely, MAPK85 activation and consequent JUN-dependent transcription. May play a role in apoptosis. Tumor suppressor. Inhibits tumor promoter-induced neoplastic transformation. Binds RNA. Ref.8 Ref.9 Ref.10 Ref.12
Subunit structure	Interacts (via MI domains) with EIF4A1 and EIF4A2 (via N-terminal domain). Heterotrimer with EIF4A1; one molecule of PDCD4 binds two molecules of EIF4A1. Interacts with EIF4G1. May form a complex with EIF4A1 and EIF4G1. The interaction between PDCD4 and EIF4A1 interferes with the interaction between EIF4A1 and EIF4G. When phosphorylated, interacts with BTRC and FBXW11 By similarity. Ref.8 Ref.12 Ref.13 Ref.14
Subcellular location	Nucleus. Cytoplasm. Note: Shuttles between the nucleus and cytoplasm. Predominantly nuclear under normal growth conditions, and when phosphorylated at Ser-457 By similarity. Exported from the nucleus in the absence of serum. Ref.8 Ref.9
Tissue specificity	Expressed ubiquitously. Highyly expressed in thymus and liver. Moderately expressed in brain, kidney and spleen; weakly in lung and heart. Expression is up- or down-regulated in response to apoptosis inducers. Regulated by many programmed cell death-inducing stimuli. Ref.1 Ref.3
Domain	Binds EIF4A1 via both MI domains. Ref.14
Post-translational modification	Polyubiquitinated, leading to its proteasomal degradation. Rapidly degraded in response to mitogens. Phosphorylation of the phosphodegron promotes interaction with BTRC and proteasomal degradation By similarity. Phosphorylated at Ser-67 by RPS6KB1 in response to mitogens; phosphorylation promotes proteasomal degradation of PDCD4 By similarity. Ref.11
Involvement in disease	Note=Decreases benign tumor development and malignant progression.
Sequence similarities	Belongs to the PDCD4 family. Contains 2 MI domains.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Nucleus
Disease	Tumor suppressor
Domain	Repeat
Ligand	RNA-binding
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cell aging Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription, DNA-dependent Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	cytosol Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	RNA binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Eif4g2	Q62448	2	EBI-296473,EBI-296494

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 469

469

Programmed cell death protein 4

PRO_0000256520

Regions

Domain

163 – 284

122

MI 1

Domain

326 – 449

124

MI 2

Motif

58 – 64

7

Nuclear localization signal Potential

Motif

70 – 76

7

Phosphodegron By similarity

Motif

448 – 454

7

Nuclear localization signal Potential

Amino acid modifications

Modified residue

67

1

Phosphoserine; by PKB and RPS6KB1 By similarity

Modified residue

76

1

Phosphoserine Ref.11

Modified residue

78

1

Phosphoserine By similarity

Modified residue

93

1

Phosphothreonine By similarity

Modified residue

94

1

Phosphoserine By similarity

Modified residue

152

1

Phosphotyrosine By similarity

Modified residue

457

1

Phosphoserine; by PKB By similarity

Experimental info

Mutagenesis

414

1

D → A: Strongly reduced interaction with EIF4A1. Ref.12

Mutagenesis

418

1

D → A: Strongly reduced interaction with EIF4A1. Ref.12

Mutagenesis

457

1

S → A or D: No effect on interaction with EIF4A1. Ref.12

Sequence conflict

232

1

S → I in BAA32356. Ref.2

Sequence conflict

232

1

S → I in BAA13072. Ref.3

Sequence conflict

369

1

V → I in BAA32356. Ref.2

Sequence conflict

369

1

V → I in BAA13072. Ref.3

Sequence conflict

414

1

D → G in BAE43115. Ref.5

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

469

Helix Strand Turn

Details...

Helix

326 – 341

16

Helix

344 – 354

11

Helix

357 – 359

3

Helix

360 – 373

14

Helix

378 – 392

15

Helix

398 – 418

21

Helix

422 – 435

14

Helix

441 – 445

5

Sequences

	Sequence		Length	Mass (Da)
	Q61823 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 6883BCE5011692F1	FASTA	469	51,702
	10 20 30 40 50 60 MDIENEQTLN VNPTDPDNLS DSLFSGDEEN AGTEEIKNEI NGNWISASTI NEARINAKAK 70 80 90 100 110 120 RRLRKNSSRD SGRGDSVSDN GSEAVRSGVA VPTSPKGRLL DRRSRSGKGR GLPKKGGAGG 130 140 150 160 170 180 KGVWGTPGQV YDVEEVDVKD PNYDDDQENC VYETVVLPLD ETAFEKTLTP IIQEYFEHGD 190 200 210 220 230 240 TNEVAEMLRD LNLGEMKSGV PVLAVSLALE GKASHREMTS KLLSDLCGTV MSTNDVEKSF 250 260 270 280 290 300 DKLLKDLPEL ALDTPRAPQL VGQFIARAVG DGILCNTYID SYKGTVDCVQ ARAALDKATV 310 320 330 340 350 360 LLSMSKGGKR KDSVWGSGGG QQPVNHLVKE IDMLLKEYLL SGDISEAEHC LKELEVPHFH 370 380 390 400 410 420 HELVYEAIVM VLESTGESAF KMILDLLKSL WKSSTITIDQ MKRGYERIYN EIPDINLDVP 430 440 450 460 HSYSVLERFV EECFQAGIIS KQLRDLCPSR GRKRFVSEGD GGRLKPESY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death." Shibahara K., Asano M., Ishida Y., Aoki T., Koike T., Honjo T. Gene 166:297-301(1995) [PubMed: 8543179] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Strain: ICR. Tissue: Thymus.
[2]	"Molecular cloning of the genes suppressed in RVC lymphoma cells by topoisomerase inhibitors." Onishi Y., Kizaki H. Biochem. Biophys. Res. Commun. 228:7-13(1996) [PubMed: 8912629] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Lymphoma.
[3]	"Cloning of the TIS gene suppressed by topoisomerase inhibitors." Onishi Y., Hashimoto S., Kizaki H. Gene 215:453-459(1998) [PubMed: 9714845] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY.
[4]	"Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus." Clee S.M., Yandell B.S., Schueler K.M., Rabaglia M.E., Richards O.C., Raines S.M., Kabara E.A., Klass D.M., Mui E.T.-K., Stapleton D.S., Gray-Keller M.P., Young M.B., Stoehr J.P., Lan H., Boronenkov I., Raess P.W., Flowers M.T., Attie A.D. Nat. Genet. 38:688-693(2006) [PubMed: 16682971] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Strain: BTBR T+ tf/J.
[5]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J and NOD. Tissue: Spleen and Testis.
[6]	"Cloning of mouse full open reading frames in Gateway(R) system entry vector (pDONR201)." Ebert L., Muenstermann E., Schatten R., Henze S., Bohn E., Mollenhauer J., Wiemann S., Schick M., Korn B. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"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]. Strain: C57BL/6. Tissue: Brain.
[8]	"The transformation suppressor Pdcd4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation." Yang H.-S., Jansen A.P., Komar A.A., Zheng X., Merrick W.C., Costes S., Lockett S.J., Sonenberg N., Colburn N.H. Mol. Cell. Biol. 23:26-37(2003) [PubMed: 12482958] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH EIF4A1 AND EIF4A2.
[9]	"The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA." Boehm M., Sawicka K., Siebrasse J.P., Brehmer-Fastnacht A., Peters R., Klempnauer K.-H. Oncogene 22:4905-4910(2003) [PubMed: 12894233] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[10]	"Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis." Jansen A.P., Camalier C.E., Colburn N.H. Cancer Res. 65:6034-6041(2005) [PubMed: 16024603] [Abstract] Cited for: FUNCTION.
[11]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed: 19367708] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-76, MASS SPECTROMETRY. Tissue: Melanoma.
[12]	"Structural basis for inhibition of translation by the tumor suppressor pdcd4." Laronde-Leblanc N., Santhanam A.N., Baker A.R., Wlodawer A., Colburn N.H. Mol. Cell. Biol. 27:147-156(2007) [PubMed: 17060447] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.15 ANGSTROMS) OF 320-469, FUNCTION, INTERACTION WITH EIF4A AND EIF4G, SUBUNIT, MUTAGENESIS OF ASP-414; ASP-418 AND SER-457.
[13]	"Structure of the C-terminal MA-3 domain of the tumour suppressor protein Pdcd4 and characterization of its interaction with eIF4A." Waters L.C., Veverka V., Bohm M., Schmedt T., Choong P.T., Muskett F.W., Klempnauer K.H., Carr M.D. Oncogene 26:4941-4950(2007) [PubMed: 17310995] [Abstract] Cited for: STRUCTURE BY NMR OF 319-449, INTERACTION WITH EIF4A1.
[14]	"Structural basis for translational inhibition by the tumour suppressor Pdcd4." Loh P.G., Yang H.S., Walsh M.A., Wang Q., Wang X., Cheng Z., Liu D., Song H. EMBO J. 28:274-285(2009) [PubMed: 19153607] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 120-469 IN COMPLEX WITH EIF4A1, SUBUNIT, DOMAIN.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

D50465 mRNA. Translation: BAA09056.1.
D86344 mRNA. Translation: BAA13072.1.
AB010139 Genomic DNA. Translation: BAA32356.1.
DQ479921 Genomic DNA. Translation: ABF51670.1.
CT010188 mRNA. Translation: CAJ18396.1.
AK134366 mRNA. Translation: BAE22118.1.
AK172654 mRNA. Translation: BAE43115.1.
BC055739 mRNA. Translation: AAH55739.1.

IPI

IPI00323064.

PIR

JC4523.

RefSeq

NP_001161963.1. NM_001168491.1.
NP_001161964.1. NM_001168492.1.
NP_035180.2. NM_011050.4.

UniGene

Mm.1605.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2HM8	NMR	-	A	319-449	[»]
2IOL	X-ray	2.00	A/B	320-469	[»]
2ION	X-ray	1.57	A	320-469	[»]
2IOS	X-ray	1.76	A	320-469	[»]
2KZT	NMR	-	B	319-449	[»]
2NSZ	X-ray	1.15	A	322-450	[»]
3EIQ	X-ray	3.50	C	120-469	[»]

ProteinModelPortal

Q61823.

SMR

Q61823. Positions 157-450.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q61823. 3 interactions.

MINT

MINT-7012023.

STRING

Q61823.

PTM databases

PhosphoSite

Q61823.

Proteomic databases

PRIDE

Q61823.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSMUST00000025931; ENSMUSP00000025931; ENSMUSG00000024975.
ENSMUST00000074371; ENSMUSP00000073975; ENSMUSG00000024975.
ENSMUST00000165617; ENSMUSP00000133135; ENSMUSG00000024975.

GeneID

18569.

KEGG

mmu:18569.

UCSC

uc008hxb.2. mouse.

Organism-specific databases

CTD

27250.

MGI

MGI:107490. Pdcd4.

Phylogenomic databases

eggNOG

roNOG08674.

GeneTree

ENSGT00390000015948.

HOGENOM

HBG714347.

HOVERGEN

HBG052841.

InParanoid

Q61823.

OMA

MSKGGKR.

OrthoDB

EOG4GMTX3.

PhylomeDB

Q61823.

Gene expression databases

ArrayExpress

Q61823.

Bgee

Q61823.

CleanEx

MM_PDCD4.

Genevestigator

Q61823.

GermOnline

ENSMUSG00000024975. Mus musculus.

Family and domain databases

InterPro

IPR016024. ARM-type_fold.
IPR003891. Initiation_fac_eIF4g_MI.
[Graphical view]

Pfam

PF02847. MA3. 2 hits.
[Graphical view]

SMART

SM00544. MA3. 2 hits.
[Graphical view]

SUPFAM

SSF48371. ARM-type_fold. 2 hits.

PROSITE

PS51366. MI. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

NextBio

294400.

SOURCE

Search...

Entry information

Entry name

PDCD4_MOUSE

Accession

Primary (citable) accession number: Q61823
Secondary accession number(s): P97296, Q3T9A9

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2006
Last sequence update:	November 1, 1996
Last modified:	November 16, 2011
This is version 102 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program