Reviewed, UniProtKB/Swiss-Prot Q96LA8 (ANM6_HUMAN)

Names and origin

Protein names

Recommended name:
    Protein arginine N-methyltransferase 6
    EC=2.1.1.-
Alternative name(s):
    Histone-arginine N-methyltransferase PRMT6
    EC=2.1.1.125
    Heterogeneous nuclear ribonucleoprotein methyltransferase-like protein 6

Gene names

Name:	PRMT6
Synonyms:	HRMT1L6

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	375 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA. Preferentially methylates arginyl residues present in a glycine and arginine-rich domain and displays preference for monomethylated substrates. Specifically mediates the asymmetric dimethylation of histone H3 'Arg-2' to form H3R2me2a. H3R2me2a represents a specific tag for epigenetic transcriptional repression and is mutually exclusive with methylation on histone H3 'Lys-4' (H3K4me2 and H3K4me3). It thereby acts as a transcription corepressor of various genes such as HOXA2. Also methylates histone H2A and H4 'Arg-3' (H2AR3me and H4R3me, respectively). Acts as a regulator of DNA base excision during DNA repair by mediating the methylation of DNA polymerase beta (POLB), leading to stimulate the polymerase activity by enhancing DNA binding and processivity. Methylates HMGA1. May play a role in innate immunity against HIV-1 in case of infection by methylating and impairing the function of various HIV-1 proteins such as Tat, Rev and Nucleocapsid protein p7 (NC). Ref.1 Ref.7 Ref.8 Ref.9 Ref.12 Ref.13 Ref.14 Ref.15
Catalytic activity	S-adenosyl-L-methionine + histone-arginine = S-adenosyl-L-homocysteine + histone-N(omega)-methyl-arginine. Ref.13 Ref.14 Ref.15
Subunit structure	Interacts with (and methylates) HIV-1 Tat, Rev and Nucleocapsid protein p7 (NC). Ref.7 Ref.8 Ref.9 Ref.12 Ref.6 Ref.10 Ref.11
Subcellular location	Nucleus. Ref.1
Tissue specificity	Highly expressed in kidney and testes. Ref.1
Post-translational modification	Automethylated. Ref.1
Sequence similarities	Belongs to the protein arginine N-methyltransferase family. PRMT6 subfamily.
Biophysicochemical properties	Kinetic parameters: KM=18.6 µM for AdoMet KM=501 µM for WGGYSRGGYGGW peptide KM=183.7 µM for WGGYSR(MMA)GGYGGW monomethylated peptide Vmax=3.3 nmol/min/mg enzyme with AdoMet as substrate Vmax=1.8 nmol/min/mg enzyme with WGGYSRGGYGGW peptide as substrate Vmax=3.2 nmol/min/mg enzyme with WGGYSR(MMA)GGYGGW monomethylated peptide as substrate

Ontologies

Keywords
Biological process	DNA damage DNA repair Host-virus interaction Transcription Transcription regulation
Cellular component	Nucleus
Coding sequence diversity	Alternative splicing
Ligand	S-adenosyl-L-methionine
Molecular function	Chromatin regulator Methyltransferase Transferase
PTM	Methylation Phosphoprotein
Technical term	Complete proteome
Gene Ontology (GO)
Biological process	base-excision repair Ref.9 Traceable author statement. Source: UniProtKB histone H3-R2 methylation Ref.13 Ref.14 Inferred from direct assay. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of transcription, DNA-dependent Ref.14 Inferred from direct assay. Source: UniProtKB peptidyl-arginine methylation, to asymmetrical-dimethyl arginine Ref.13 Ref.14 Inferred from direct assay. Source: UniProtKB transcription Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	nucleus Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	histone binding Ref.13 Ref.14 Inferred from direct assay. Source: UniProtKB histone methyltransferase activity (H2A-R3 specific) Ref.14 Inferred from direct assay. Source: UniProtKB histone methyltransferase activity (H3-R2 specific) Ref.13 Ref.14 Inferred from direct assay. Source: UniProtKB histone methyltransferase activity (H4-R3 specific) Ref.14 Inferred from direct assay. Source: UniProtKB protein-arginine omega-N asymmetric methyltransferase activity Ref.1 Ref.7 Ref.13 Ref.14 Inferred from direct assay. Source: UniProtKB protein-arginine omega-N monomethyltransferase activity Ref.1 Ref.7 Ref.9 Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
HMGA1	P17096-1	2	EBI-912440,EBI-746854
HMGA1	P17096-2	1	EBI-912440,EBI-746858
HMGA2	P52926	1	EBI-912440,EBI-912511

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96LA8-1)

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 2 (identifier: Q96LA8-2)

The sequence of this isoform differs from the canonical sequence as follows:
     26-109: GAEREAALER...CAQAGARRVY → D

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 375	375	Protein arginine N-methyltransferase 6		PRO_0000212332
Regions
	Compositional bias	12 – 20	9	Poly-Gly
Sites
	Binding site	57	1	S-adenosyl-L-methionine By similarity
	Binding site	66	1	S-adenosyl-L-methionine By similarity
	Binding site	90	1	S-adenosyl-L-methionine; via carbonyl oxygen By similarity
	Binding site	112	1	S-adenosyl-L-methionine By similarity
	Binding site	141	1	S-adenosyl-L-methionine By similarity
Amino acid modifications
	Modified residue	21	1	Phosphothreonine Ref.17
Natural variations
	Alternative sequence	26 – 109	84	GAERE…ARRVY → D in isoform 2.		VSP_037465
	Natural variant	194	1	A → V: dbSNP rs2232016. Ref.5		VAR_057150
Experimental info
	Mutagenesis	86 – 88	3	VLD → KLA in PRMT6dn; abolishes histone methyltransferase H3R2me2a activity. Ref.13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: 40AAEC7342C08A38	FASTA	375	41,938
	10 20 30 40 50 60 MSQPKKRKLE SGGGGEGGEG TEEEDGAERE AALERPRRTK RERDQLYYEC YSDVSVHEEM 70 80 90 100 110 120 IADRVRTDAY RLGILRNWAA LRGKTVLDVG AGTGILSIFC AQAGARRVYA VEASAIWQQA 130 140 150 160 170 180 REVVRFNGLE DRVHVLPGPV ETVELPEQVD AIVSEWMGYG LLHESMLSSV LHARTKWLKE 190 200 210 220 230 240 GGLLLPASAE LFIAPISDQM LEWRLGFWSQ VKQHYGVDMS CLEGFATRCL MGHSEIVVQG 250 260 270 280 290 300 LSGEDVLARP QRFAQLELSR AGLEQELEAG VGGRFRCSCY GSAPMHGFAI WFQVTFPGGE 310 320 330 340 350 360 SEKPLVLSTS PFHPATHWKQ ALLYLNEPVQ VEQDTDVSGE ITLLPSRDNP RRLRVLLRYK 370 VGDQEEKTKD FAMED
	Isoform 2. Checksum: 9E6341283024795C	FASTA	292	32,509
	10 20 30 40 50 60 MSQPKKRKLE SGGGGEGGEG TEEEDDAVEA SAIWQQAREV VRFNGLEDRV HVLPGPVETV 70 80 90 100 110 120 ELPEQVDAIV SEWMGYGLLH ESMLSSVLHA RTKWLKEGGL LLPASAELFI APISDQMLEW 130 140 150 160 170 180 RLGFWSQVKQ HYGVDMSCLE GFATRCLMGH SEIVVQGLSG EDVLARPQRF AQLELSRAGL 190 200 210 220 230 240 EQELEAGVGG RFRCSCYGSA PMHGFAIWFQ VTFPGGESEK PLVLSTSPFH PATHWKQALL 250 260 270 280 290 YLNEPVQVEQ DTDVSGEITL LPSRDNPRRL RVLLRYKVGD QEEKTKDFAM ED

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity." Frankel A., Yadav N., Lee J., Branscombe T.L., Clarke S., Bedford M.T. J. Biol. Chem. 277:3537-3543(2002) [PubMed: 11724789] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AUTOMETHYLATION. Tissue: Kidney.
[2]	"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] (ISOFORM 2), NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 25-375 (ISOFORM 1). Tissue: Hippocampus and Teratocarcinoma.
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[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] (ISOFORM 1), VARIANT VAL-194. Tissue: Blood, Eye and Placenta.
[6]	"Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression." Boulanger M.C., Liang C., Russell R.S., Lin R., Bedford M.T., Wainberg M.A., Richard S. J. Virol. 79:124-131(2005) [PubMed: 15596808] [Abstract] Cited for: INTERACTION WITH HIV-1 TAT.
[7]	"Protein arginine methyltransferase 6 specifically methylates the nonhistone chromatin protein HMGA1a." Miranda T.B., Webb K.J., Edberg D.D., Reeves R., Clarke S. Biochem. Biophys. Res. Commun. 336:831-835(2005) [PubMed: 16157300] [Abstract] Cited for: FUNCTION, INTERACTION WITH HMGA1.
[8]	"Dynamics of human protein arginine methyltransferase 1(PRMT1) in vivo." Herrmann F., Lee J., Bedford M.T., Fackelmayer F.O. J. Biol. Chem. 280:38005-38010(2005) [PubMed: 16159886] [Abstract] Cited for: FUNCTION, INTERACTION WITH HMGA1.
[9]	"Arginine methylation regulates DNA polymerase beta." El-Andaloussi N., Valovka T., Toueille M., Steinacher R., Focke F., Gehrig P., Covic M., Hassa P.O., Schaer P., Huebscher U., Hottiger M.O. Mol. Cell 22:51-62(2006) [PubMed: 16600869] [Abstract] Cited for: FUNCTION, INTERACTION WITH POLB.
[10]	"PRMT6 diminishes HIV-1 Rev binding to and export of viral RNA." Invernizzi C.F., Xie B., Richard S., Wainberg M.A. Retrovirology 3:93-93(2006) [PubMed: 17176473] [Abstract] Cited for: INTERACTION WITH HIV-1 REV.
[11]	"Arginine methylation of the HIV-1 nucleocapsid protein results in its diminished function." Invernizzi C.F., Xie B., Frankel F.A., Feldhammer M., Roy B.B., Richard S., Wainberg M.A. AIDS 21:795-805(2007) [PubMed: 17415034] [Abstract] Cited for: INTERACTION WITH HIV-1 NC.
[12]	"Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat Interactions with both cyclin T1 and the Tat transactivation region." Xie B., Invernizzi C.F., Richard S., Wainberg M.A. J. Virol. 81:4226-4234(2007) [PubMed: 17267505] [Abstract] Cited for: FUNCTION, INTERACTION WITH HIV-1 TAT.
[13]	"Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive." Guccione E., Bassi C., Casadio F., Martinato F., Cesaroni M., Schuchlautz H., Luescher B., Amati B. Nature 449:933-937(2007) [PubMed: 17898714] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF 86-VAL--ASP-88.
[14]	"PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation." Hyllus D., Stein C., Schnabel K., Schiltz E., Imhof A., Dou Y., Hsieh J., Bauer U.M. Genes Dev. 21:3369-3380(2007) [PubMed: 18079182] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY.
[15]	"Arginine methylation of the histone H3 tail impedes effector binding." Iberg A.N., Espejo A., Cheng D., Kim D., Michaud-Levesque J., Richard S., Bedford M.T. J. Biol. Chem. 283:3006-3010(2008) [PubMed: 18077460] [Abstract] Cited for: FUNCTION, CATALYTIC ACTIVITY.
[16]	"A kinetic study of human protein arginine N-methyltransferase 6 reveals a distributive mechanism." Lakowski T.M., Frankel A. J. Biol. Chem. 283:10015-10025(2008) [PubMed: 18263580] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES.
[17]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-21, MASS SPECTROMETRY.
[18]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AY043278 mRNA. Translation: AAK85733.1. AK001421 mRNA. Translation: BAA91681.1. Different initiation. AK295541 mRNA. Translation: BAG58450.1. AL355539 Genomic DNA. Translation: CAI19090.1. CH471156 Genomic DNA. Translation: EAW51248.1. BC002729 mRNA. Translation: AAH02729.3. Different initiation. BC063446 mRNA. Translation: AAH63446.2. Different initiation. BC073866 mRNA. Translation: AAH73866.1.
IPI	IPI00102128. IPI00909110.
RefSeq	NP_060607.2.
UniGene	Hs.26006
3D structure databases
HSSP	HSSP built from PDB template 1ORI based on UniProtKB Q63009.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96LA8. 7 interactions.
STRING	Q96LA8.
PTM databases
PhosphoSite	Q96LA8.
Proteomic databases
PRIDE	Q96LA8.
Genome annotation databases
Ensembl	ENST00000361318; ENSP00000355145; ENSG00000198890; Homo sapiens. [Genome view] ENST00000370078; ENSP00000359095; ENSG00000198890; Homo sapiens. [Genome view]
GeneID	55170.
KEGG	hsa:55170.
UCSC	uc001dvb.1. human.
Organism-specific databases
CTD	55170.
GeneCards	GC01P107400.
H-InvDB	HIX0000828.
HGNC	HGNC:18241. PRMT6.
MIM	608274. gene.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q96LA8.
HOVERGEN	Q96LA8.
OMA	GRFRFSC.
Gene expression databases
ArrayExpress	Q96LA8.
Bgee	Q96LA8.
CleanEx	HS_PRMT6.
Genevestigator	Q96LA8.
GermOnline	ENSG00000198890. Homo sapiens.
Family and domain databases
InterPro	IPR013216. Methyltransf_11. [Graphical view]
Pfam	PF08241. Methyltransf_11. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	58949.
SOURCE	Search...

Entry information

Entry name

ANM6_HUMAN

Accession

Primary (citable) accession number: Q96LA8
Secondary accession number(s): A3KME1 , B4DID8, Q5T5Y5, Q6DKI4, Q9NVR8

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 27, 2002
Last sequence update:	December 1, 2001
Last modified:	November 3, 2009
This is version 70 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.