P03255 (E1A_ADE05) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names	Recommended name: Early E1A 32 kDa protein
Organism	Human adenovirus C serotype 5 (HAdV-5) (Human adenovirus 5) [Complete proteome]
Taxonomic identifier	28285 [NCBI]
Taxonomic lineage	Viruses › dsDNA viruses, no RNA stage › Adenoviridae › Mastadenovirus › Human adenovirus C
Virus host	Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	289 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E1A protein has both transforming and trans-activating activities. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle. Disrupts the function of host retinoblastoma protein RB1/pRb and isoform early E1A 26 kDa protein stabilizes TP53, which are key regulators of the cell cycle. Induces the disassembly of the E2F1 transcription factors from RB1 by direct competition for the same binding site on RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes. Inactivation of the ability of RB1 to arrest the cell cycle is critical for cellular transformation, uncontrolled cellular growth and proliferation induced by viral infection. Stimulation of progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication. Interaction with RBX1 and CUL1 inhibits ubiquitination of the proteins targeted by SCF(FBXW7) ubiquitin ligase complex, and may be linked to unregulated host cell proliferation. The tumorigenesis-restraining activity of E1A may be related to the disruption of the host CtBP-CtIP complex through the CtBP binding motif. Ref.6 Ref.8 Ref.9 Ref.10
Subunit structure	Interacts with host UBE2I; this interaction interferes with polySUMOylation Probable. Interaction with host RB1 induces the aberrant dissociation of RB1-E2F1 complex thereby disrupting RB1's activity. Interacts with host ATF7; the interaction enhances ATF7-mediated viral transactivation activity which requires the zinc binding domains of both proteins By similarity. Isoform early E1A 32 kDa protein and isoform early E1A 26 kDa protein interact (via N-terminus) with CUL1 and E3 ubiquitin ligase RBX1; these interactions inhibit RBX1-CUL1-dependent elongation reaction of ubiquitin chains. Interacts (via N-terminus) with the SCF(FBXW7) complex; this interaction results in inhibition of the ubiquitin ligase activity of the SCF(FBXW7) complex, ubiquitination of SCF(FBXW7) target proteins being diminished. Interacts (via PXLXP motif) with host ZMYND11/BS69 (via MYND-type zinc finger); this interaction inhibits E1A mediated transactivation. Ref.5 Ref.7 Ref.9 Ref.10
Subcellular location	Host nucleus Potential.
Sequence similarities	Belongs to the adenoviridae E1A protein family.

Ontologies

Keywords
Biological process	G1/S host cell cycle checkpoint dysregulation by virus Host gene expression shutoff by virus Host transcription shutoff by virus Host-virus interaction Inhibition of host STAT1 by virus Inhibition of host innate immune response by virus Inhibition of host interferon signaling pathway by virus Inhibition of host transcription initiation by virus Modulation of host E3 ubiquitin ligases by virus Modulation of host cell cycle by virus Modulation of host ubiquitin pathway by virus Transcription Transcription regulation Viral immunoevasion
Cellular component	Host nucleus
Coding sequence diversity	Alternative splicing
Developmental stage	Early protein
Disease	Oncogene
Domain	Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Activator
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological_process	modulation by virus of host G1/S transition checkpoint Inferred from electronic annotation. Source: UniProtKB-KW modulation by virus of host ubiquitin-protein ligase activity Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of cell proliferation Inferred from direct assay PubMed 9054499. Source: BHF-UCL regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host DNA-dependent transcription, initiation Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host STAT1 activity Inferred from electronic annotation. Source: UniProtKB-KW suppression by virus of host type I interferon-mediated signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	host cell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Isoforms are derived from the E1 region of the genome.

Isoform early E1A 32 kDa protein (identifier: P03255-1)

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.

Isoform early E1A 26 kDa protein (identifier: P03255-2)

The sequence of this isoform differs from the canonical sequence as follows:
     140-185: Missing.

Note: No experimental confirmation available.

Isoform early E1A 6 kDa protein (identifier: P03255-3)

The sequence of this isoform differs from the canonical sequence as follows:
     29-55: ADNLPPPSHFEPPTLHELYDLDVTAPE → CLNLSLSPSQNRSLQDLPAVLKWRLLS
     56-289: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 289

289

Early E1A 32 kDa protein

PRO_0000221694

Regions

Zinc finger

154 – 174

21

Potential

Region

41 – 49

9

Interaction with RB1 in competition with E2F1 Probable

Region

76 – 140

65

Interaction with UBE2I

Motif

113 – 117

5

PXLXP motif, interaction with host ZMYND11

Motif

122 – 126

5

LXCXE motif, interaction with host RB1 Potential

Motif

279 – 283

5

PXDLS motif, CTBP-binding

Motif

285 – 289

5

Nuclear localization signal Potential

Amino acid modifications

Modified residue

89

1

Phosphoserine; by host Ref.3

Modified residue

219

1

Phosphoserine; by host Ref.3

Modified residue

231

1

Phosphoserine; by host Ref.3

Natural variations

Alternative sequence

29 – 55

27

ADNLP…VTAPE → CLNLSLSPSQNRSLQDLPAV LKWRLLS in isoform early E1A 6 kDa protein.

VSP_028918

Alternative sequence

56 – 289

234

Missing in isoform early E1A 6 kDa protein.

VSP_028919

Alternative sequence

140 – 185

46

Missing in isoform early E1A 26 kDa protein.

VSP_000198

Experimental info

Mutagenesis

115

1

L → A: Complete loss of interaction with host ZMYND11. Ref.7

Mutagenesis

122

1

L → I: Abolishes binding to UBE2I. Ref.5

Mutagenesis

154

1

C → S: Loss of transactivation. Ref.4

Mutagenesis

157

1

C → S: Loss of transactivation. Ref.4

Mutagenesis

171

1

C → S: Loss of transactivation. Ref.4

Mutagenesis

174

1

C → S: Loss of transactivation. Ref.4

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

289

Helix Strand Turn

Details...

Helix

43 – 46

4

Helix

59 – 63

5

Beta strand

68 – 70

3

Helix

72 – 74

3

Helix

80 – 82

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform early E1A 32 kDa protein [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 8C5997A3908C40D7	FASTA	289	31,851
	10 20 30 40 50 60 MRHIICHGGV ITEEMAASLL DQLIEEVLAD NLPPPSHFEP PTLHELYDLD VTAPEDPNEE 70 80 90 100 110 120 AVSQIFPDSV MLAVQEGIDL LTFPPAPGSP EPPHLSRQPE QPEQRALGPV SMPNLVPEVI 130 140 150 160 170 180 DLTCHEAGFP PSDDEDEEGE EFVLDYVEHP GHGCRSCHYH RRNTGDPDIM CSLCYMRTCG 190 200 210 220 230 240 MFVYSPVSEP EPEPEPEPEP ARPTRRPKMA PAILRRPTSP VSRECNSSTD SCDSGPSNTP 250 260 270 280 PEIHPVVPLC PIKPVAVRVG GRRQAVECIE DLLNEPGQPL DLSCKRPRP
	Isoform early E1A 26 kDa protein [UniParc]. Checksum: CA355781A92A4D42	FASTA	243	26,452
	10 20 30 40 50 60 MRHIICHGGV ITEEMAASLL DQLIEEVLAD NLPPPSHFEP PTLHELYDLD VTAPEDPNEE 70 80 90 100 110 120 AVSQIFPDSV MLAVQEGIDL LTFPPAPGSP EPPHLSRQPE QPEQRALGPV SMPNLVPEVI 130 140 150 160 170 180 DLTCHEAGFP PSDDEDEEGP VSEPEPEPEP EPEPARPTRR PKMAPAILRR PTSPVSRECN 190 200 210 220 230 240 SSTDSCDSGP SNTPPEIHPV VPLCPIKPVA VRVGGRRQAV ECIEDLLNEP GQPLDLSCKR PRP
	Isoform early E1A 6 kDa protein [UniParc]. Checksum: 001555BAD0415F3A	FASTA	55	6,156
	10 20 30 40 50 MRHIICHGGV ITEEMAASLL DQLIEEVLCL NLSLSPSQNR SLQDLPAVLK WRLLS

References

[1]	"The nucleotide sequence of the transforming early region E1 of adenovirus type 5 DNA." van Ormondt H., Maat J., van Beveren C.P. Gene 11:299-309(1980) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS EARLY E1A 32 KDA PROTEIN; EARLY E1A 26 KDA PROTEIN AND EARLY E1A 6 KDA PROTEIN).
[2]	"The sequence of the genome of adenovirus type 5 and its comparison with the genome of adenovirus type 2." Chroboczek J., Bieber F., Jacrot B. Virology 186:280-285(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Identification of the phosphorylation sites in early region 1A proteins of adenovirus type 5 by amino acid sequencing of peptide fragments." Tremblay M.L., McGlade C.J., Gerber G.E., Branton P.E. J. Biol. Chem. 263:6375-6383(1988) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-89; SER-219 AND SER-231.
[4]	"Conversion of the E1A Cys4 zinc finger to a nonfunctional His2,Cys2 zinc finger by a single point mutation." Webster L.C., Zhang K., Chance B., Ayene I., Culp J.S., Huang W.-J., Wu F.Y.-H., Ricciardi R.P. Proc. Natl. Acad. Sci. U.S.A. 88:9989-9993(1991) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF CYS-154; CYS-157; CYS-171 AND CYS-174.
[5]	"mUBC9, a novel adenovirus E1A-interacting protein that complements a yeast cell cycle defect." Hateboer G., Hijmans E.M., Nooij J.B.D., Schlenker S., Jentsch S., Bernards R. J. Biol. Chem. 271:25906-25911(1996) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN UBE2I, MUTAGENESIS OF LEU-122.
[6]	"Stabilization of p53 by adenovirus E1A occurs through its amino-terminal region by modification of the ubiquitin-proteasome pathway." Nakajima T., Morita K., Tsunoda H., Imajoh-Ohmi S., Tanaka H., Yasuda H., Oda K. J. Biol. Chem. 273:20036-20045(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION OF ISOFORM EARLY E1A 26 KDA PROTEIN.
[7]	"The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif." Ansieau S., Leutz A. J. Biol. Chem. 277:4906-4910(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH HUMAN ZMYND11/BS69, MUTAGENESIS OF LEU-115.
[8]	"Viral oncoproteins E1A and E7 and cellular LxCxE proteins repress SUMO modification of the retinoblastoma tumor suppressor." Ledl A., Schmidt D., Muller S. Oncogene 24:3810-3818(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[9]	"Adenovirus E1A inhibits SCF(Fbw7) ubiquitin ligase." Isobe T., Hattori T., Kitagawa K., Uchida C., Kotake Y., Kosugi I., Oda T., Kitagawa M. J. Biol. Chem. 284:27766-27779(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HOST RBX1 AND HOST CUL1, INTERACTION WITH SCF(FBXW7) COMPLEX.
[10]	"Identification of a molecular recognition feature in the E1A oncoprotein that binds the SUMO conjugase UBC9 and likely interferes with polySUMOylation." Yousef A.F., Fonseca G.J., Pelka P., Ablack J.N., Walsh C., Dick F.A., Bazett-Jones D.P., Shaw G.S., Mymryk J.S. Oncogene 29:4693-4704(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HOST UBE2I.
[11]	"Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor." Liu X., Marmorstein R. Genes Dev. 21:2711-2716(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.67 ANGSTROMS) OF 40-49 IN COMPLEX WITH HUMAN RB1.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M73260 Genomic DNA. No translation available.
X02996 Genomic DNA. Translation: CAB40663.1.
X02996 Genomic DNA. Translation: CAB40664.1.
X02996 Genomic DNA. Translation: CAB40665.1.

PIR

ERAD65. A03825.
Q2AD5. C03824.

RefSeq

AP_000197.1. AC_000008.1.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KJE	NMR	-	B	53-91	[»]
2R7G	X-ray	1.67	B/D/E	40-49	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-40736N.

IntAct

P03255. 2 interactions.

MINT

MINT-87547.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Family and domain databases

InterPro

IPR014410. Aden_E1A.
IPR003853. Adeno_E1A.
[Graphical view]

Pfam

PF02703. Adeno_E1A. 1 hit.
[Graphical view]

PIRSF

PIRSF003669. Aden_E1A. 1 hit.

ProtoNet

Search...

Other

EvolutionaryTrace

P03255.

Entry information

Entry name

E1A_ADE05

Accession

Primary (citable) accession number: P03255
Secondary accession number(s): P06438, Q64825, Q64826

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 1, 2013
This is version 89 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Viral Protein Annotation Program