ID   METL9_HUMAN             Reviewed;         318 AA.
AC   Q9H1A3; Q8NBT8; Q9BWJ7; Q9H1A2; Q9Y390;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   01-MAR-2001, sequence version 1.
DT   27-MAR-2024, entry version 140.
DE   RecName: Full=Protein-L-histidine N-pros-methyltransferase {ECO:0000305};
DE            EC=2.1.1.- {ECO:0000269|PubMed:33563959, ECO:0000269|PubMed:34562450};
DE   AltName: Full=DORA reverse strand protein {ECO:0000303|PubMed:11132146};
DE            Short=DREV {ECO:0000303|PubMed:11132146};
DE            Short=DREV1 {ECO:0000303|PubMed:11132146};
DE   AltName: Full=Methyltransferase-like protein 9 {ECO:0000303|PubMed:33563959};
DE            Short=hMETTL9 {ECO:0000303|PubMed:33563959};
DE   Flags: Precursor;
GN   Name=METTL9 {ECO:0000303|PubMed:33563959,
GN   ECO:0000312|HGNC:HGNC:24586};
GN   Synonyms=DREV {ECO:0000303|PubMed:11132146};
GN   ORFNames=CGI-81 {ECO:0000303|PubMed:10810093};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX   PubMed=11132146; DOI=10.1007/s002510000259;
RA   Bates E.E.M., Kissenpfennig A., Peronne C., Mattei M.-G., Fossiez F.,
RA   Malissen B., Lebecque S.;
RT   "The mouse and human IGSF6 (DORA) genes map to the inflammatory bowel
RT   disease 1 locus and are embedded in an intron of a gene of unknown
RT   function.";
RL   Immunogenetics 52:112-120(2000).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Embryo;
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC   TISSUE=Eye;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 27-318 (ISOFORM 2).
RX   PubMed=10810093; DOI=10.1101/gr.10.5.703;
RA   Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.;
RT   "Identification of novel human genes evolutionarily conserved in
RT   Caenorhabditis elegans by comparative proteomics.";
RL   Genome Res. 10:703-713(2000).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX   PubMed=34562450; DOI=10.1016/j.jbc.2021.101230;
RA   Daitoku H., Someya M., Kako K., Hayashi T., Tajima T., Haruki H.,
RA   Sekiguchi N., Uetake T., Akimoto Y., Fukamizu A.;
RT   "siRNA screening identifies METTL9 as a histidine Npi-methyltransferase
RT   that targets the proinflammatory protein S100A9.";
RL   J. Biol. Chem. 297:101230-101230(2021).
RN   [7]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP   GLU-174.
RX   PubMed=33563959; DOI=10.1038/s41467-020-20670-7;
RA   Davydova E., Shimazu T., Schuhmacher M.K., Jakobsson M.E.,
RA   Willemen H.L.D.M., Liu T., Moen A., Ho A.Y.Y., Malecki J., Schroer L.,
RA   Pinto R., Suzuki T., Groensberg I.A., Sohtome Y., Akakabe M., Weirich S.,
RA   Kikuchi M., Olsen J.V., Dohmae N., Umehara T., Sodeoka M., Siino V.,
RA   McDonough M.A., Eijkelkamp N., Schofield C.J., Jeltsch A., Shinkai Y.,
RA   Falnes P.O.;
RT   "The methyltransferase METTL9 mediates pervasive 1-methylhistidine
RT   modification in mammalian proteomes.";
RL   Nat. Commun. 12:891-891(2021).
CC   -!- FUNCTION: Protein-histidine N-methyltransferase that specifically
CC       catalyzes 1-methylhistidine (pros-methylhistidine) methylation of
CC       target proteins (PubMed:33563959, PubMed:34562450). Mediates
CC       methylation of proteins with a His-x-His (HxH) motif (where 'x' is
CC       preferably a small amino acid) (PubMed:33563959). Catalyzes methylation
CC       of target proteins such as S100A9, NDUFB3, SLC39A5, SLC39A7, ARMC6 and
CC       DNAJB12; 1-methylhistidine modification may affect the binding of zinc
CC       and other metals to its target proteins (PubMed:33563959,
CC       PubMed:34562450). Constitutes the main methyltransferase for the 1-
CC       methylhistidine modification in cell (PubMed:33563959).
CC       {ECO:0000269|PubMed:33563959, ECO:0000269|PubMed:34562450}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-histidyl-[protein] + S-adenosyl-L-methionine = H(+) +
CC         N(pros)-methyl-L-histidyl-[protein] + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:67076, Rhea:RHEA-COMP:9745, Rhea:RHEA-COMP:17184,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:29979, ChEBI:CHEBI:43903,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789;
CC         Evidence={ECO:0000269|PubMed:33563959, ECO:0000269|PubMed:34562450};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67077;
CC         Evidence={ECO:0000269|PubMed:33563959, ECO:0000269|PubMed:34562450};
CC   -!- INTERACTION:
CC       Q9H1A3; Q9HB07: MYG1; NbExp=3; IntAct=EBI-2804879, EBI-709754;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC       {ECO:0000269|PubMed:34562450, ECO:0000305|PubMed:33563959}.
CC       Mitochondrion {ECO:0000305|PubMed:33563959}. Note=Colocalizes with
CC       membranous compartments such as the endoplasmic reticulum and
CC       mitochondria. {ECO:0000269|PubMed:33563959}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q9H1A3-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q9H1A3-2; Sequence=VSP_030997;
CC   -!- SIMILARITY: Belongs to the METTL9 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAD34076.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR   EMBL; AJ278578; CAC20438.1; -; mRNA.
DR   EMBL; AJ278577; CAC20437.1; -; mRNA.
DR   EMBL; AJ278581; CAC20439.1; -; Genomic_DNA.
DR   EMBL; AK075237; BAC11490.1; -; mRNA.
DR   EMBL; AK074529; BAC11042.1; -; mRNA.
DR   EMBL; AK075022; BAC11356.1; -; mRNA.
DR   EMBL; CH878403; EAW50517.1; -; Genomic_DNA.
DR   EMBL; CH878403; EAW50518.1; -; Genomic_DNA.
DR   EMBL; BC000195; AAH00195.2; -; mRNA.
DR   EMBL; AF151839; AAD34076.1; ALT_INIT; mRNA.
DR   CCDS; CCDS10598.2; -. [Q9H1A3-1]
DR   CCDS; CCDS45440.1; -. [Q9H1A3-2]
DR   RefSeq; NP_001070648.1; NM_001077180.2. [Q9H1A3-2]
DR   RefSeq; NP_001275588.1; NM_001288659.1.
DR   RefSeq; NP_001275589.1; NM_001288660.1.
DR   RefSeq; NP_057109.3; NM_016025.4. [Q9H1A3-1]
DR   PDB; 7Y9C; X-ray; 2.10 A; A/B=46-318.
DR   PDB; 7YF2; X-ray; 1.69 A; A/B=46-318.
DR   PDB; 7YF3; X-ray; 3.43 A; A/B=46-318.
DR   PDB; 7YF4; X-ray; 2.75 A; A/B=46-318.
DR   PDB; 8GZE; X-ray; 3.40 A; A/B=53-318.
DR   PDB; 8GZF; X-ray; 2.50 A; A/B=53-318.
DR   PDBsum; 7Y9C; -.
DR   PDBsum; 7YF2; -.
DR   PDBsum; 7YF3; -.
DR   PDBsum; 7YF4; -.
DR   PDBsum; 8GZE; -.
DR   PDBsum; 8GZF; -.
DR   AlphaFoldDB; Q9H1A3; -.
DR   SMR; Q9H1A3; -.
DR   BioGRID; 119297; 94.
DR   IntAct; Q9H1A3; 18.
DR   MINT; Q9H1A3; -.
DR   STRING; 9606.ENSP00000350874; -.
DR   GlyCosmos; Q9H1A3; 1 site, No reported glycans.
DR   GlyGen; Q9H1A3; 1 site.
DR   iPTMnet; Q9H1A3; -.
DR   PhosphoSitePlus; Q9H1A3; -.
DR   BioMuta; METTL9; -.
DR   DMDM; 74718034; -.
DR   EPD; Q9H1A3; -.
DR   jPOST; Q9H1A3; -.
DR   MassIVE; Q9H1A3; -.
DR   MaxQB; Q9H1A3; -.
DR   PaxDb; 9606-ENSP00000350874; -.
DR   PeptideAtlas; Q9H1A3; -.
DR   ProteomicsDB; 80382; -. [Q9H1A3-1]
DR   ProteomicsDB; 80383; -. [Q9H1A3-2]
DR   Pumba; Q9H1A3; -.
DR   Antibodypedia; 25721; 41 antibodies from 12 providers.
DR   DNASU; 51108; -.
DR   Ensembl; ENST00000358154.8; ENSP00000350874.3; ENSG00000197006.15. [Q9H1A3-1]
DR   Ensembl; ENST00000396014.8; ENSP00000379335.4; ENSG00000197006.15. [Q9H1A3-2]
DR   GeneID; 51108; -.
DR   KEGG; hsa:51108; -.
DR   MANE-Select; ENST00000358154.8; ENSP00000350874.3; NM_016025.5; NP_057109.3.
DR   UCSC; uc002dje.4; human. [Q9H1A3-1]
DR   AGR; HGNC:24586; -.
DR   CTD; 51108; -.
DR   DisGeNET; 51108; -.
DR   GeneCards; METTL9; -.
DR   HGNC; HGNC:24586; METTL9.
DR   HPA; ENSG00000197006; Low tissue specificity.
DR   MIM; 609388; gene.
DR   neXtProt; NX_Q9H1A3; -.
DR   OpenTargets; ENSG00000197006; -.
DR   PharmGKB; PA145148428; -.
DR   VEuPathDB; HostDB:ENSG00000197006; -.
DR   eggNOG; KOG3987; Eukaryota.
DR   GeneTree; ENSGT00390000013648; -.
DR   InParanoid; Q9H1A3; -.
DR   OMA; FDVIACN; -.
DR   OrthoDB; 8628at2759; -.
DR   PhylomeDB; Q9H1A3; -.
DR   TreeFam; TF314187; -.
DR   PathwayCommons; Q9H1A3; -.
DR   SignaLink; Q9H1A3; -.
DR   BioGRID-ORCS; 51108; 15 hits in 1151 CRISPR screens.
DR   ChiTaRS; METTL9; human.
DR   GenomeRNAi; 51108; -.
DR   Pharos; Q9H1A3; Tdark.
DR   PRO; PR:Q9H1A3; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; Q9H1A3; Protein.
DR   Bgee; ENSG00000197006; Expressed in secondary oocyte and 208 other cell types or tissues.
DR   ExpressionAtlas; Q9H1A3; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR   GO; GO:0106370; F:protein-L-histidine N-pros-methyltransferase activity; IDA:UniProtKB.
DR   GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR   CDD; cd02440; AdoMet_MTases; 1.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR   InterPro; IPR007884; METL9.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   PANTHER; PTHR12890; DREV PROTEIN; 1.
DR   PANTHER; PTHR12890:SF0; PROTEIN-L-HISTIDINE N-PROS-METHYLTRANSFERASE; 1.
DR   Pfam; PF05219; DREV; 1.
DR   SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
DR   Genevisible; Q9H1A3; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Endoplasmic reticulum; Glycoprotein;
KW   Methyltransferase; Mitochondrion; Reference proteome; Signal; Transferase.
FT   SIGNAL          1..18
FT                   /evidence="ECO:0000255"
FT   CHAIN           19..318
FT                   /note="Protein-L-histidine N-pros-methyltransferase"
FT                   /id="PRO_0000317490"
FT   CARBOHYD        35
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         251
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:10810093,
FT                   ECO:0000303|PubMed:11132146, ECO:0000303|PubMed:14702039"
FT                   /id="VSP_030997"
FT   MUTAGEN         174
FT                   /note="E->A: Abolished protein-L-histidine
FT                   N-pros-methyltransferase activity."
FT                   /evidence="ECO:0000269|PubMed:33563959"
FT   CONFLICT        43..44
FT                   /note="PA -> RS (in Ref. 5; AAD34076)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        57
FT                   /note="Y -> C (in Ref. 2; BAC11490)"
FT                   /evidence="ECO:0000305"
FT   HELIX           54..56
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           61..63
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           66..69
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          71..73
FT                   /evidence="ECO:0007829|PDB:8GZE"
FT   HELIX           79..92
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           95..108
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   TURN            109..111
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           114..121
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          126..128
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           131..138
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          146..152
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           160..163
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           164..166
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          167..172
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           177..185
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          189..191
FT                   /evidence="ECO:0007829|PDB:8GZF"
FT   TURN            193..195
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           196..198
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          199..201
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          203..210
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   TURN            212..214
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           218..228
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   TURN            231..233
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          235..243
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           251..253
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   HELIX           269..282
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          285..298
FT                   /evidence="ECO:0007829|PDB:7YF2"
FT   STRAND          304..317
FT                   /evidence="ECO:0007829|PDB:7YF2"
SQ   SEQUENCE   318 AA;  36536 MW;  81DEF9CC78342229 CRC64;
     MRLLAGWLCL SLASVWLARR MWTLRSPLTR SLYVNMTSGP GGPAAAAGGR KENHQWYVCN
     REKLCESLQA VFVQSYLDQG TQIFLNNSIE KSGWLFIQLY HSFVSSVFSL FMSRTSINGL
     LGRGSMFVFS PDQFQRLLKI NPDWKTHRLL DLGAGDGEVT KIMSPHFEEI YATELSETMI
     WQLQKKKYRV LGINEWQNTG FQYDVISCLN LLDRCDQPLT LLKDIRSVLE PTRGRVILAL
     VLPFHPYVEN VGGKWEKPSE ILEIKGQNWE EQVNSLPEVF RKAGFVIEAF TRLPYLCEGD
     MYNDYYVLDD AVFVLKPV
//