UniProt Accession

 PML_HUMAN; P29590; E9PBR7; P29591; P29592; P29593; Q00755; Q15959; Q59FP9; Q8WUA0; Q96S41; Q9BPW2; Q9BWP7; Q9BZX6; Q9BZX7; Q9BZX8; Q9BZX9; Q9BZY0; Q9BZY2; Q9BZY3 

Genbank Protein ID

 S50913; M79462; M79463; M79464; X63131; M73778; M80185; AF230401; AF230402; AF230403; AF230405; AF230406; AF230407; AF230408; AF230409; AF230410; AF230411; BT009911; AB209411; AC013486; AC108137; BC000080; BC020994; X64800; AB067754 

Genbank Nucleotide ID

 AAB19601.2; AAA60388.1; AAA60351.1; AAA60390.1; CAA44841.1; AAA60125.1; AAA60352.1; AAG50180.1; AAG50181.1; AAG50182.1; AAG50184.1; AAG50185.1; AAG50186.1; AAG50187.1; AAG50188.1; AAG50189.1; AAG50190.1; AAP88913.1; BAD92648.1; AAH00080.2; AAH20994.1; CAA46026.1; BAB62809.1 

Protein Name

 Protein PML 

Protein Synonyms/Alias

 Promyelocytic leukemia protein; RING finger protein 71; Tripartite motif-containing protein 19 

Gene Name

 PML 

Gene Synonyms/Alias

 MYL; PP8675; RNF71; TRIM19 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
65	QQCQAEAKCPKLLPC	sumoylation	[1, 2, 3, 4, 5, 6]
65	QQCQAEAKCPKLLPC	ubiquitination	[7]
68	QAEAKCPKLLPCLHT	ubiquitination	[7]
160	EAHQWFLKHEARPLA	sumoylation	[1, 2, 3, 4, 6, 8]
183	EFLDGTRKTNNIFCS	ubiquitination	[7]
226	DSSHSELKCDISAEI	ubiquitination	[7]
337	SALVQRMKCYASDQE	ubiquitination	[7]
380	TDGFDEFKVRLQDLS	sumoylation	[4]
380	TDGFDEFKVRLQDLS	ubiquitination	[7, 9, 10, 11]
394	SSCITQGKDAAVSKK	ubiquitination	[7, 9, 10, 11, 12, 13]
400	GKDAAVSKKASPEAA	sumoylation	[4]
400	GKDAAVSKKASPEAA	ubiquitination	[7, 9, 11]
401	KDAAVSKKASPEAAS	ubiquitination	[7, 9, 11]
426	PEEAERVKAQVQALG	ubiquitination	[7]
476	SNTTTAQKRKCSQTQ	ubiquitination	[7, 9, 10, 11]
478	TTTAQKRKCSQTQCP	ubiquitination	[7]
487	SQTQCPRKVIKMESE	acetylation	[14]
490	QCPRKVIKMESEEGK	sumoylation	[1, 2, 3, 4, 15, 16]
497	KMESEEGKEARLARS	sumoylation	[4]
497	KMESEEGKEARLARS	ubiquitination	[9]
515	QPRPSTSKAVSPPHL	acetylation	[14]
616	PLVFFDLKIDNETQK	sumoylation	[5]
623	KIDNETQKISQLAAV	ubiquitination	[7, 9, 11, 12, 13, 17]
725	VPGASSFKLKNLAQT	ubiquitination	[7]
727	GASSFKLKNLAQTYL	ubiquitination	[7]

Reference

 [1] Identification of three major sentrinization sites in PML.
 Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET.
 J Biol Chem. 1998 Oct 9;273(41):26675-82. [PMID: 9756909]
 [2] Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation.
 Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honoré N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de Thé H.
 J Exp Med. 2001 Jun 18;193(12):1361-71. [PMID: 11413191]
 [3] Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin.
 Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D'Arpa P.
 J Biol Chem. 2002 Oct 18;277(42):40020-6. [PMID: 12149243]
 [4] A novel proteomics approach to identify SUMOylated proteins and their modification sites in human cells.
 Galisson F, Mahrouche L, Courcelles M, Bonneil E, Meloche S, Chelbi-Alix MK, Thibault P.
 Mol Cell Proteomics. 2011 Feb;10(2):M110.004796. [PMID: 21098080]
 [5] A viral ubiquitin ligase has substrate preferential SUMO targeted ubiquitin ligase activity that counteracts intrinsic antiviral defence.
 Boutell C, Cuchet-Lourenço D, Vanni E, Orr A, Glass M, McFarlane S, Everett RD.
 PLoS Pathog. 2011 Sep;7(9):e1002245. [PMID: 21949651]
 [6] The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.
 de Thé H, Le Bras M, Lallemand-Breitenbach V.
 J Cell Biol. 2012 Jul 9;198(1):11-21. [PMID: 22778276]
 [7] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [8] Pathways of retinoic acid- or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission.
 Zhu J, Lallemand-Breitenbach V, de Thé H.
 Oncogene. 2001 Oct 29;20(49):7257-65. [PMID: 11704854]
 [9] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
 [10] Methods for quantification of in vivo changes in protein ubiquitination following proteasome and deubiquitinase inhibition.
 Udeshi ND, Mani DR, Eisenhaure T, Mertins P, Jaffe JD, Clauser KR, Hacohen N, Carr SA.
 Mol Cell Proteomics. 2012 May;11(5):148-59. [PMID: 22505724]
 [11] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [12] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [13] Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass.
 Povlsen LK, Beli P, Wagner SA, Poulsen SL, Sylvestersen KB, Poulsen JW, Nielsen ML, Bekker-Jensen S, Mailand N, Choudhary C.
 Nat Cell Biol. 2012 Oct;14(10):1089-98. [PMID: 23000965]
 [14] Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis.
 Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T.
 J Biol Chem. 2008 Sep 5;283(36):24420-5. [PMID: 18621739]
 [15] Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif.
 Matic I, Schimmel J, Hendriks IA, van Santen MA, van de Rijke F, van Dam H, Gnad F, Mann M, Vertegaal AC.
 Mol Cell. 2010 Aug 27;39(4):641-52. [PMID: 20797634]
 [16] Promyelocytic leukemia isoform IV confers resistance to encephalomyocarditis virus via the sequestration of 3D polymerase in nuclear bodies.
 Maroui MA, Pampin M, Chelbi-Alix MK.
 J Virol. 2011 Dec;85(24):13164-73. [PMID: 21994459]
 [17] Integrated proteomic analysis of post-translational modifications by serial enrichment.
 Mertins P, Qiao JW, Patel J, Udeshi ND, Clauser KR, Mani DR, Burgess MW, Gillette MA, Jaffe JD, Carr SA.
 Nat Methods. 2013 Jul;10(7):634-7. [PMID: 23749302] 

Functional Description

 Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma- irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration. 

Sequence Annotation

 ZN_FING 57 92 RING-type.
 ZN_FING 124 166 B box-type 1; atypical.
 ZN_FING 183 236 B box-type 2.
 REGION 448 555 Interaction with PER2.
 REGION 476 490 Nuclear localization signal.
 REGION 556 562 Sumo interaction motif (SIM).
 METAL 57 57 Zinc 1.
 METAL 60 60 Zinc 1.
 METAL 72 72 Zinc 2.
 METAL 74 74 Zinc 2.
 METAL 77 77 Zinc 1.
 METAL 80 80 Zinc 1.
 METAL 88 88 Zinc 2.
 METAL 91 91 Zinc 2.
 MOD_RES 8 8 Phosphoserine; by HIPK2.
 MOD_RES 28 28 Phosphothreonine; by MAPK1.
 MOD_RES 36 36 Phosphoserine; by HIPK2 and MAPK1.
 MOD_RES 38 38 Phosphoserine; by HIPK2 and MAPK1.
 MOD_RES 40 40 Phosphoserine; by MAPK1.
 MOD_RES 42 42 Phosphothreonine.
 MOD_RES 117 117 Phosphoserine; by CHEK2.
 MOD_RES 403 403 Phosphoserine; by MAPK1 and MAPK7.
 MOD_RES 409 409 Phosphothreonine; by MAPK7.
 MOD_RES 487 487 N6-acetyllysine.
 MOD_RES 504 504 Phosphoserine (By similarity).
 MOD_RES 505 505 Phosphoserine; by MAPK1.
 MOD_RES 515 515 N6-acetyllysine (Probable).
 MOD_RES 518 518 Phosphoserine; by CDK1 and CDK2.
 MOD_RES 527 527 Phosphoserine; by MAPK1.
 MOD_RES 530 530 Phosphoserine; by MAPK1.
 MOD_RES 535 535 Phosphoserine.
 MOD_RES 565 565 Phosphoserine; by CK2.
 CROSSLNK 65 65 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 160 160 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 380 380 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 400 400 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 401 401 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 476 476 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 490 490 Glycyl lysine isopeptide (Lys-Gly)
 CROSSLNK 497 497 Glycyl lysine isopeptide (Lys-Gly)  

Keyword

 3D-structure; Acetylation; Activator; Alternative splicing; Antiviral defense; Apoptosis; Chromosomal rearrangement; Coiled coil; Complete proteome; Cytoplasm; DNA-binding; Endoplasmic reticulum; Endosome; Host-virus interaction; Immunity; Innate immunity; Isopeptide bond; Membrane; Metal-binding; Nucleus; Phosphoprotein; Polymorphism; Proto-oncogene; Reference proteome; Repeat; Transcription; Transcription regulation; Tumor suppressor; Ubl conjugation; Zinc; Zinc-finger. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 882 AA 

Protein Sequence

Gene Ontology

 GO:0005737; C:cytoplasm; IDA:UniProtKB.
 GO:0005829; C:cytosol; ISS:UniProtKB.
 GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
 GO:0042406; C:extrinsic to endoplasmic reticulum membrane; ISS:UniProtKB.
 GO:0016363; C:nuclear matrix; IDA:UniProtKB.
 GO:0031965; C:nuclear membrane; IDA:UniProtKB.
 GO:0005730; C:nucleolus; IDA:UniProtKB.
 GO:0005634; C:nucleus; IDA:UniProtKB.
 GO:0016605; C:PML body; IDA:UniProtKB.
 GO:0050897; F:cobalt ion binding; IDA:UniProtKB.
 GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
 GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
 GO:0003713; F:transcription coactivator activity; IDA:UniProtKB.
 GO:0008270; F:zinc ion binding; IDA:UniProtKB.
 GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Compara.
 GO:0060444; P:branching involved in mammary gland duct morphogenesis; IEA:Compara.
 GO:0007050; P:cell cycle arrest; IDA:UniProtKB.
 GO:0045165; P:cell fate commitment; IEA:Compara.
 GO:0090398; P:cellular senescence; IDA:UniProtKB.
 GO:0007182; P:common-partner SMAD protein phosphorylation; IEA:Compara.
 GO:0051607; P:defense response to virus; IEA:UniProtKB-KW.
 GO:0006977; P:DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; ISS:UniProtKB.
 GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; ISS:UniProtKB.
 GO:0006917; P:induction of apoptosis; IDA:UniProtKB.
 GO:0060333; P:interferon-gamma-mediated signaling pathway; TAS:Reactome.
 GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IDA:UniProtKB.
 GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; ISS:UniProtKB.
 GO:0051457; P:maintenance of protein location in nucleus; IDA:MGI.
 GO:0030099; P:myeloid cell differentiation; IEA:Compara.
 GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
 GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
 GO:0008285; P:negative regulation of cell proliferation; IMP:BHF-UCL.
 GO:0045930; P:negative regulation of mitotic cell cycle; IDA:UniProtKB.
 GO:2000059; P:negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
 GO:0051974; P:negative regulation of telomerase activity; IMP:UniProtKB.
 GO:0032211; P:negative regulation of telomere maintenance via telomerase; IMP:UniProtKB.
 GO:0045892; P:negative regulation of transcription, DNA-dependent; IDA:UniProtKB.
 GO:0032938; P:negative regulation of translation in response to oxidative stress; IDA:UniProtKB.
 GO:0030578; P:PML body organization; IDA:UniProtKB.
 GO:0002230; P:positive regulation of defense response to virus by host; IMP:UniProtKB.
 GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IMP:UniProtKB.
 GO:0031065; P:positive regulation of histone deacetylation; IDA:UniProtKB.
 GO:0043161; P:proteasomal ubiquitin-dependent protein catabolic process; IDA:UniProtKB.
 GO:0006461; P:protein complex assembly; IDA:UniProtKB.
 GO:0050821; P:protein stabilization; IDA:UniProtKB.
 GO:0006605; P:protein targeting; IDA:UniProtKB.
 GO:0010522; P:regulation of calcium ion transport into cytosol; ISS:UniProtKB.
 GO:2000779; P:regulation of double-strand break repair; IMP:UniProtKB.
 GO:0045343; P:regulation of MHC class I biosynthetic process; IEA:Compara.
 GO:0001932; P:regulation of protein phosphorylation; ISS:UniProtKB.
 GO:0010332; P:response to gamma radiation; IEA:Compara.
 GO:0001666; P:response to hypoxia; IDA:UniProtKB.
 GO:0009411; P:response to UV; IEA:Compara.
 GO:0048384; P:retinoic acid receptor signaling pathway; IEA:Compara.
 GO:0007184; P:SMAD protein import into nucleus; IEA:Compara.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Compara.
 GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW. 

Interpro

 IPR021978; DUF3583.
 IPR000315; Znf_B-box.
 IPR001841; Znf_RING.
 IPR013083; Znf_RING/FYVE/PHD.
 IPR017907; Znf_RING_CS. 

Pfam

 PF12126; DUF3583
 PF00643; zf-B_box 

SMART

 SM00336; BBOX
 SM00184; RING 

PROSITE

 PS50119; ZF_BBOX
 PS00518; ZF_RING_1
 PS50089; ZF_RING_2 

PRINTS