MET16_HUMAN
ID MET16_HUMAN Reviewed; 562 AA.
AC Q86W50; D3DTI8; Q86TE5; Q96T16; Q9BVG7;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 2.
DT 03-AUG-2022, entry version 137.
DE RecName: Full=RNA N6-adenosine-methyltransferase METTL16 {ECO:0000305};
DE AltName: Full=Methyltransferase 10 domain-containing protein {ECO:0000303|Ref.16};
DE AltName: Full=Methyltransferase-like protein 16 {ECO:0000303|PubMed:27872311};
DE AltName: Full=N6-adenosine-methyltransferase METTL16;
DE EC=2.1.1.348 {ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:30197297, ECO:0000269|PubMed:30197299, ECO:0000269|PubMed:33428944};
DE AltName: Full=U6 small nuclear RNA (adenine-(43)-N(6))-methyltransferase {ECO:0000305};
DE EC=2.1.1.346 {ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:29051200, ECO:0000269|PubMed:32266935};
GN Name=METTL16 {ECO:0000303|PubMed:27872311, ECO:0000312|HGNC:HGNC:28484};
GN Synonyms=METT10D {ECO:0000303|Ref.16, ECO:0000312|HGNC:HGNC:28484};
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 [LARGE SCALE MRNA] (ISOFORM 1).
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Spinal cord;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ASN-479.
RC TISSUE=Muscle, and Uterus;
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 [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-329, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-329, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-329, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [10]
RP FUNCTION, RNA-BINDING, AND SUBCELLULAR LOCATION.
RX PubMed=27872311; DOI=10.1073/pnas.1614759113;
RA Brown J.A., Kinzig C.G., DeGregorio S.J., Steitz J.A.;
RT "Methyltransferase-like protein 16 binds the 3'-terminal triple helix of
RT MALAT1 long noncoding RNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:14013-14018(2016).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, DOMAIN, AND MUTAGENESIS OF 185-PRO-PRO-186
RP AND PHE-187.
RX PubMed=28525753; DOI=10.1016/j.cell.2017.05.003;
RA Pendleton K.E., Chen B., Liu K., Hunter O.V., Xie Y., Tu B.P., Conrad N.K.;
RT "The U6 snRNA m(6)A methyltransferase METTL16 regulates SAM synthetase
RT intron retention.";
RL Cell 169:824-835(2017).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH LARP7 AND MEPCE.
RX PubMed=29051200; DOI=10.15252/embr.201744940;
RA Warda A.S., Kretschmer J., Hackert P., Lenz C., Urlaub H., Hoebartner C.,
RA Sloan K.E., Bohnsack M.T.;
RT "Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets
RT pre-mRNAs and various non-coding RNAs.";
RL EMBO Rep. 18:2004-2014(2017).
RN [13]
RP SUBCELLULAR LOCATION.
RX PubMed=31940410; DOI=10.1371/journal.pone.0227647;
RA Nance D.J., Satterwhite E.R., Bhaskar B., Misra S., Carraway K.R.,
RA Mansfield K.D.;
RT "Characterization of METTL16 as a cytoplasmic RNA binding protein.";
RL PLoS ONE 15:e0227647-e0227647(2020).
RN [14]
RP FUNCTION.
RX PubMed=33930289; DOI=10.1016/j.cell.2021.03.062;
RA Mendel M., Delaney K., Pandey R.R., Chen K.M., Wenda J.M., Vaagboe C.B.,
RA Steiner F.A., Homolka D., Pillai R.S.;
RT "Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA
RT splicing.";
RL Cell 0:0-0(2021).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=33428944; DOI=10.1016/j.jbc.2021.100270;
RA Yu D., Kaur G., Blumenthal R.M., Zhang X., Cheng X.;
RT "Enzymatic characterization of three human RNA adenosine methyltransferases
RT reveals diverse substrate affinities and reaction optima.";
RL J. Biol. Chem. 296:100270-100270(2021).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 39-291 IN COMPLEX WITH
RP S-ADENOSYL-L-HOMOCYSTEINE.
RG Structural genomics consortium (SGC);
RT "The crystal structure of human methyltransferase 10 domain-containing
RT protein.";
RL Submitted (JUN-2006) to the PDB data bank.
RN [17] {ECO:0007744|PDB:6GFK, ECO:0007744|PDB:6GFN, ECO:0007744|PDB:6GT5}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 41-291 IN COMPLEX WITH
RP S-ADENOSYL-L-HOMOCYSTEINE, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF
RP 5-LYS--LYS-16; LYS-5; ARG-10; ARG-12; LYS-14; LYS-16; LYS-26; LYS-31;
RP LYS-47; ARG-82; 185-PRO-PRO-186; PHE-187; 200-ARG--ARG-204;
RP 202-PRO-PRO-207; ARG-279 AND ARG-282.
RX PubMed=30197299; DOI=10.1016/j.molcel.2018.08.004;
RA Mendel M., Chen K.M., Homolka D., Gos P., Pandey R.R., McCarthy A.A.,
RA Pillai R.S.;
RT "Methylation of structured RNA by the m6A writer METTL16 is essential for
RT mouse embryonic development.";
RL Mol. Cell 71:986-1000(2018).
RN [18] {ECO:0007744|PDB:6DU4, ECO:0007744|PDB:6DU5}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-310 IN COMPLEX WITH RNA,
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, MUTAGENESIS OF ASN-39;
RP ARG-82; GLU-133; LYS-163; MET-167 AND ASN-184, VARIANT CYS-110, AND
RP CHARACTERIZATION OF VARIANT CYS-110.
RX PubMed=30197297; DOI=10.1016/j.molcel.2018.07.025;
RA Doxtader K.A., Wang P., Scarborough A.M., Seo D., Conrad N.K., Nam Y.;
RT "Structural basis for regulation of METTL16, an S-adenosylmethionine
RT homeostasis factor.";
RL Mol. Cell 71:1001-1011(2018).
RN [19] {ECO:0007744|PDB:6B91, ECO:0007744|PDB:6B92}
RP X-RAY CRYSTALLOGRAPHY (1.94 ANGSTROMS) OF 1-291 IN COMPLEX WITH
RP S-ADENOSYL-L-HOMOCYSTEINE.
RX PubMed=29593291; DOI=10.1038/s41598-018-23608-8;
RA Ruszkowska A., Ruszkowski M., Dauter Z., Brown J.A.;
RT "Structural insights into the RNA methyltransferase domain of METTL16.";
RL Sci. Rep. 8:5311-5311(2018).
RN [20] {ECO:0007744|PDB:6M1U}
RP X-RAY CRYSTALLOGRAPHY (2.79 ANGSTROMS) OF 310-562, FUNCTION, CATALYTIC
RP ACTIVITY, AND DOMAIN.
RX PubMed=32266935; DOI=10.1093/nar/gkaa227;
RA Aoyama T., Yamashita S., Tomita K.;
RT "Mechanistic insights into m6A modification of U6 snRNA by human METTL16.";
RL Nucleic Acids Res. 48:5157-5168(2020).
CC -!- FUNCTION: RNA N6-methyltransferase that methylates adenosine residues
CC at the N(6) position of a subset of RNAs and is involved in S-adenosyl-
CC L-methionine homeostasis by regulating expression of MAT2A transcripts
CC (PubMed:28525753, PubMed:30197299, PubMed:30197297, PubMed:33428944,
CC PubMed:33930289). Able to N6-methylate a subset of mRNAs and U6 small
CC nuclear RNAs (U6 snRNAs) (PubMed:28525753). In contrast to the METTL3-
CC METTL14 heterodimer, only able to methylate a limited number of RNAs:
CC requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA
CC structure (PubMed:28525753, PubMed:30197299, PubMed:30197297). Plays a
CC key role in S-adenosyl-L-methionine homeostasis by mediating N6-
CC methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in
CC presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A
CC mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA,
CC preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby
CC inhibiting splicing and protein production of S-adenosylmethionine
CC synthase (PubMed:28525753, PubMed:33930289). In S-adenosyl-L-
CC methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA
CC but stalls due to the lack of a methyl donor, preventing N6-methylation
CC and promoting expression of MAT2A (PubMed:28525753). In addition to
CC mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6
CC snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs
CC (PubMed:28525753, PubMed:29051200, PubMed:32266935). Also able to bind
CC various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA
CC (PubMed:29051200). Specifically binds the 3'-end of the MALAT1 long
CC non-coding RNA (PubMed:27872311). {ECO:0000269|PubMed:27872311,
CC ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:29051200,
CC ECO:0000269|PubMed:30197297, ECO:0000269|PubMed:30197299,
CC ECO:0000269|PubMed:32266935, ECO:0000269|PubMed:33428944}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine in U6 snRNA + S-adenosyl-L-methionine = H(+) + N(6)-
CC methyladenosine in U6 snRNA + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:52808, Rhea:RHEA-COMP:13573, Rhea:RHEA-COMP:13574,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.346;
CC Evidence={ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:29051200,
CC ECO:0000269|PubMed:32266935};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52809;
CC Evidence={ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:29051200,
CC ECO:0000269|PubMed:32266935};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)-
CC methyladenosine in mRNA + H(+) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:55584, Rhea:RHEA-COMP:12414, Rhea:RHEA-COMP:12417,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74411, ChEBI:CHEBI:74449; EC=2.1.1.348;
CC Evidence={ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:30197297,
CC ECO:0000269|PubMed:30197299, ECO:0000269|PubMed:33428944};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55585;
CC Evidence={ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:30197297,
CC ECO:0000269|PubMed:30197299, ECO:0000269|PubMed:33428944};
CC -!- ACTIVITY REGULATION: Methyltransferase activity is autoinhibited by the
CC K-loop region that blocks S-adenosyl-L-methionine-binding
CC (PubMed:30197297). Upon activation, K-loop changes conformation,
CC allowing S-adenosyl-L-methionine-binding and subsequent
CC methyltransferase activity (PubMed:30197297). mRNA N6-adenosine-
CC methyltransferase activity is inhibited by zinc (PubMed:33428944).
CC {ECO:0000269|PubMed:30197297, ECO:0000269|PubMed:33428944}.
CC -!- SUBUNIT: Interacts with MEPCE (PubMed:29051200). Interacts with LARP7
CC (PubMed:29051200). {ECO:0000269|PubMed:29051200}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:27872311,
CC ECO:0000269|PubMed:31940410}. Cytoplasm {ECO:0000269|PubMed:31940410}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q86W50-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q86W50-2; Sequence=VSP_029340, VSP_029341;
CC -!- DOMAIN: The VCR (vertebrate conserved) regions bind the first hairpin
CC of MAT2A mRNAs (PubMed:28525753). The VCR regions interact with the
CC internal stem-loop within U6 snRNAs, inducing the conformational
CC rearrangement of the A43-containing region of U6 snRNA, thereby
CC modifying the RNA structure to become suitable for productive catalysis
CC by the methyltransferase region (PubMed:32266935).
CC {ECO:0000269|PubMed:28525753, ECO:0000269|PubMed:32266935}.
CC -!- DOMAIN: The K-loop region occludes the S-adenosyl-L-methionine-binding
CC pocket (PubMed:30197297). Upon activation, conformation of the K-loop
CC changes, allowing S-adenosyl-L-methionine-binding (PubMed:30197297).
CC {ECO:0000269|PubMed:30197297}.
CC -!- SIMILARITY: Belongs to the methyltransferase superfamily. METTL16/RlmF
CC family. {ECO:0000305}.
CC -!- CAUTION: According to a report, N6-methylation of MAT2A affects MAT2A
CC mRNA stability instead of preventing splicing (By similarity). However,
CC it was later shown that N6-methylation of MAT2A transcripts prevents
CC recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting
CC splicing and protein production (PubMed:33930289).
CC {ECO:0000250|UniProtKB:Q9CQG2, ECO:0000269|PubMed:33930289}.
CC -!- CAUTION: Stoichiometry of the protein is unclear. According to two
CC reports, the methyltransferase acts as a monomer (PubMed:30197299,
CC PubMed:30197297). According to a another paper, it acts as a homodimer
CC (PubMed:29593291). {ECO:0000269|PubMed:29593291,
CC ECO:0000269|PubMed:30197297, ECO:0000269|PubMed:30197299}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAB55094.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305};
CC Sequence=CAD89999.2; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK027410; BAB55094.1; ALT_SEQ; mRNA.
DR EMBL; AL832612; CAD89999.2; ALT_FRAME; mRNA.
DR EMBL; AC006435; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC015799; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471108; EAW90537.1; -; Genomic_DNA.
DR EMBL; CH471108; EAW90538.1; -; Genomic_DNA.
DR EMBL; BC001213; AAH01213.1; -; mRNA.
DR EMBL; BC050603; AAH50603.1; -; mRNA.
DR CCDS; CCDS42232.1; -. [Q86W50-1]
DR RefSeq; NP_076991.3; NM_024086.3. [Q86W50-1]
DR PDB; 2H00; X-ray; 2.00 A; A/B/C=40-291.
DR PDB; 6B91; X-ray; 1.94 A; A=1-291.
DR PDB; 6B92; X-ray; 2.10 A; A=1-291.
DR PDB; 6DU4; X-ray; 1.70 A; A=1-310.
DR PDB; 6DU5; X-ray; 3.01 A; A=2-310.
DR PDB; 6GFK; X-ray; 2.30 A; A/B/C=41-291.
DR PDB; 6GFN; X-ray; 2.86 A; A=1-291.
DR PDB; 6GT5; X-ray; 2.45 A; A/B=1-291.
DR PDB; 6M1U; X-ray; 2.79 A; A=310-562.
DR PDBsum; 2H00; -.
DR PDBsum; 6B91; -.
DR PDBsum; 6B92; -.
DR PDBsum; 6DU4; -.
DR PDBsum; 6DU5; -.
DR PDBsum; 6GFK; -.
DR PDBsum; 6GFN; -.
DR PDBsum; 6GT5; -.
DR PDBsum; 6M1U; -.
DR AlphaFoldDB; Q86W50; -.
DR SMR; Q86W50; -.
DR BioGRID; 122519; 37.
DR IntAct; Q86W50; 5.
DR STRING; 9606.ENSP00000263092; -.
DR iPTMnet; Q86W50; -.
DR PhosphoSitePlus; Q86W50; -.
DR BioMuta; METTL16; -.
DR DMDM; 269849619; -.
DR EPD; Q86W50; -.
DR jPOST; Q86W50; -.
DR MassIVE; Q86W50; -.
DR MaxQB; Q86W50; -.
DR PaxDb; Q86W50; -.
DR PeptideAtlas; Q86W50; -.
DR PRIDE; Q86W50; -.
DR ProteomicsDB; 70116; -. [Q86W50-1]
DR ProteomicsDB; 70117; -. [Q86W50-2]
DR Antibodypedia; 5377; 266 antibodies from 25 providers.
DR DNASU; 79066; -.
DR Ensembl; ENST00000263092.11; ENSP00000263092.5; ENSG00000127804.13. [Q86W50-1]
DR GeneID; 79066; -.
DR KEGG; hsa:79066; -.
DR MANE-Select; ENST00000263092.11; ENSP00000263092.5; NM_024086.4; NP_076991.3.
DR UCSC; uc002fut.4; human. [Q86W50-1]
DR CTD; 79066; -.
DR DisGeNET; 79066; -.
DR GeneCards; METTL16; -.
DR HGNC; HGNC:28484; METTL16.
DR HPA; ENSG00000127804; Low tissue specificity.
DR neXtProt; NX_Q86W50; -.
DR OpenTargets; ENSG00000127804; -.
DR PharmGKB; PA142671460; -.
DR VEuPathDB; HostDB:ENSG00000127804; -.
DR eggNOG; KOG2912; Eukaryota.
DR GeneTree; ENSGT00390000016694; -.
DR HOGENOM; CLU_027534_0_0_1; -.
DR InParanoid; Q86W50; -.
DR OMA; TEFCQGH; -.
DR OrthoDB; 1358504at2759; -.
DR PhylomeDB; Q86W50; -.
DR TreeFam; TF313132; -.
DR BRENDA; 2.1.1.346; 2681.
DR PathwayCommons; Q86W50; -.
DR SignaLink; Q86W50; -.
DR BioGRID-ORCS; 79066; 681 hits in 1045 CRISPR screens.
DR ChiTaRS; METTL16; human.
DR EvolutionaryTrace; Q86W50; -.
DR GenomeRNAi; 79066; -.
DR Pharos; Q86W50; Tbio.
DR PRO; PR:Q86W50; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q86W50; protein.
DR Bgee; ENSG00000127804; Expressed in calcaneal tendon and 183 other tissues.
DR ExpressionAtlas; Q86W50; baseline and differential.
DR Genevisible; Q86W50; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0052907; F:23S rRNA (adenine(1618)-N(6))-methyltransferase activity; IBA:GO_Central.
DR GO; GO:0001734; F:mRNA (N6-adenosine)-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
DR GO; GO:0035613; F:RNA stem-loop binding; IDA:UniProtKB.
DR GO; GO:0120048; F:U6 snRNA (adenine-(43)-N(6))-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0030629; F:U6 snRNA 3'-end binding; IDA:UniProtKB.
DR GO; GO:0006402; P:mRNA catabolic process; ISS:UniProtKB.
DR GO; GO:0061157; P:mRNA destabilization; ISS:UniProtKB.
DR GO; GO:0080009; P:mRNA methylation; IDA:UniProtKB.
DR GO; GO:1905869; P:negative regulation of 3'-UTR-mediated mRNA stabilization; IDA:UniProtKB.
DR GO; GO:0010608; P:post-transcriptional regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0048024; P:regulation of mRNA splicing, via spliceosome; IDA:UniProtKB.
DR GO; GO:0070475; P:rRNA base methylation; IBA:GO_Central.
DR GO; GO:0006556; P:S-adenosylmethionine biosynthetic process; IDA:UniProtKB.
DR GO; GO:0120049; P:snRNA (adenine-N6)-methylation; IDA:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR017182; METTL16/PsiM.
DR InterPro; IPR010286; METTL16/RlmF.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR13393; PTHR13393; 1.
DR Pfam; PF05971; Methyltransf_10; 1.
DR PIRSF; PIRSF037350; Mtase_ZK1128_prd; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Methyltransferase; Nucleus;
KW Phosphoprotein; Reference proteome; RNA-binding; S-adenosyl-L-methionine;
KW Transferase.
FT CHAIN 1..562
FT /note="RNA N6-adenosine-methyltransferase METTL16"
FT /id="PRO_0000310767"
FT REGION 17..20
FT /note="RNA-binding"
FT /evidence="ECO:0000269|PubMed:30197297,
FT ECO:0007744|PDB:6DU4, ECO:0007744|PDB:6DU5"
FT REGION 163..167
FT /note="K-loop"
FT /evidence="ECO:0000269|PubMed:30197297"
FT REGION 199..211
FT /note="RNA-binding"
FT /evidence="ECO:0000269|PubMed:30197297,
FT ECO:0007744|PDB:6DU4, ECO:0007744|PDB:6DU5"
FT REGION 250..254
FT /note="RNA-binding"
FT /evidence="ECO:0000269|PubMed:30197297,
FT ECO:0007744|PDB:6DU4, ECO:0007744|PDB:6DU5"
FT REGION 277..283
FT /note="RNA-binding"
FT /evidence="ECO:0000269|PubMed:30197297,
FT ECO:0007744|PDB:6DU4, ECO:0007744|PDB:6DU5"
FT REGION 289..400
FT /note="VCR 1"
FT /evidence="ECO:0000269|PubMed:28525753"
FT REGION 402..498
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 514..562
FT /note="VCR 2"
FT /evidence="ECO:0000269|PubMed:28525753"
FT COMPBIAS 478..495
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 82
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29593291,
FT ECO:0000269|PubMed:30197299, ECO:0000269|Ref.16,
FT ECO:0007744|PDB:2H00, ECO:0007744|PDB:6B92,
FT ECO:0007744|PDB:6GFK, ECO:0007744|PDB:6GFN"
FT BINDING 110
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:30197299, ECO:0000269|Ref.16,
FT ECO:0007744|PDB:2H00, ECO:0007744|PDB:6GFK,
FT ECO:0007744|PDB:6GFN"
FT BINDING 114
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:30197299,
FT ECO:0007744|PDB:6GFN"
FT BINDING 133
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29593291,
FT ECO:0000269|PubMed:30197299, ECO:0000269|Ref.16,
FT ECO:0007744|PDB:2H00, ECO:0007744|PDB:6B92,
FT ECO:0007744|PDB:6GFK, ECO:0007744|PDB:6GFN"
FT BINDING 164
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29593291,
FT ECO:0000269|PubMed:30197299, ECO:0000269|Ref.16,
FT ECO:0007744|PDB:2H00, ECO:0007744|PDB:6B92,
FT ECO:0007744|PDB:6GFK, ECO:0007744|PDB:6GFN"
FT BINDING 184
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:30197299, ECO:0000269|Ref.16,
FT ECO:0007744|PDB:2H00, ECO:0007744|PDB:6GFK,
FT ECO:0007744|PDB:6GFN"
FT MOD_RES 329
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:23186163"
FT MOD_RES 463
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9CQG2"
FT VAR_SEQ 214..224
FT /note="GITEIMAEGGE -> DSLEPGRWRLQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_029340"
FT VAR_SEQ 225..562
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_029341"
FT VARIANT 110
FT /note="G -> C (found in patients with large intestine
FT cancer; abolished methyltransferase activity)"
FT /evidence="ECO:0000269|PubMed:30197297"
FT /id="VAR_081134"
FT VARIANT 479
FT /note="S -> N (in dbSNP:rs17834783)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_037086"
FT MUTAGEN 5..16
FT /note="KSMHARNRYKDK->ASMHAANAYADA: Abolished
FT methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 5
FT /note="K->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 5
FT /note="K->E: Reduced methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 10
FT /note="R->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 10
FT /note="R->D,E: Reduced methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 12
FT /note="R->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 14
FT /note="K->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 16
FT /note="K->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 26
FT /note="K->A: Does not affect methyltransferase activity;
FT when associated with A-31."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 31
FT /note="K->A: Does not affect methyltransferase activity;
FT when associated with A-26."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 39
FT /note="N->A: Does not affect methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197297"
FT MUTAGEN 47
FT /note="K->E: Reduced methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 82
FT /note="R->A,E: Abolished methyltransferase activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:30197297,
FT ECO:0000269|PubMed:30197299"
FT MUTAGEN 133
FT /note="E->A: Abolished methyltransferase activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:30197297"
FT MUTAGEN 163
FT /note="K->A: Increased methyltransferase activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:30197297"
FT MUTAGEN 167
FT /note="M->A: Increased methyltransferase activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:30197297"
FT MUTAGEN 184
FT /note="N->A: Abolished methyltransferase activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:30197297"
FT MUTAGEN 185..186
FT /note="PP->AA: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:28525753,
FT ECO:0000269|PubMed:30197299"
FT MUTAGEN 187
FT /note="F->G: Abolishes methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:28525753,
FT ECO:0000269|PubMed:30197299"
FT MUTAGEN 200..204
FT /note="RNPRR->ENPEE: Abolished methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 202..207
FT /note="PRRPPP->ARRAAA: Does not affect methyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 279
FT /note="R->E: Abolished methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT MUTAGEN 282
FT /note="R->E: Abolished methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:30197299"
FT CONFLICT 39
FT /note="N -> D (in Ref. 1; BAB55094)"
FT /evidence="ECO:0000305"
FT CONFLICT 214
FT /note="G -> A (in Ref. 2; CAD89999)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="S -> R (in Ref. 1; BAB55094)"
FT /evidence="ECO:0000305"
FT STRAND 5..7
FT /evidence="ECO:0007829|PDB:6B91"
FT TURN 12..15
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 20..26
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 28..31
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 34..36
FT /evidence="ECO:0007829|PDB:6GT5"
FT STRAND 40..44
FT /evidence="ECO:0007829|PDB:6GT5"
FT HELIX 49..64
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 79..93
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 95..97
FT /evidence="ECO:0007829|PDB:6B91"
FT HELIX 98..100
FT /evidence="ECO:0007829|PDB:2H00"
FT STRAND 105..110
FT /evidence="ECO:0007829|PDB:6DU4"
FT TURN 112..115
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 116..125
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 128..133
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 136..148
FT /evidence="ECO:0007829|PDB:6DU4"
FT TURN 152..154
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 155..159
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 161..165
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 166..169
FT /evidence="ECO:0007829|PDB:6B91"
FT STRAND 178..183
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 188..190
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 191..195
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 215..218
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 219..222
FT /evidence="ECO:0007829|PDB:2H00"
FT HELIX 223..238
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 239..241
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 242..250
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 252..254
FT /evidence="ECO:0007829|PDB:6DU4"
FT HELIX 255..264
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 268..279
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 281..288
FT /evidence="ECO:0007829|PDB:6DU4"
FT STRAND 291..293
FT /evidence="ECO:0007829|PDB:6DU5"
FT STRAND 312..316
FT /evidence="ECO:0007829|PDB:6M1U"
FT HELIX 318..328
FT /evidence="ECO:0007829|PDB:6M1U"
FT HELIX 338..352
FT /evidence="ECO:0007829|PDB:6M1U"
FT STRAND 356..360
FT /evidence="ECO:0007829|PDB:6M1U"
FT STRAND 366..375
FT /evidence="ECO:0007829|PDB:6M1U"
FT STRAND 514..525
FT /evidence="ECO:0007829|PDB:6M1U"
FT STRAND 528..537
FT /evidence="ECO:0007829|PDB:6M1U"
FT HELIX 542..559
FT /evidence="ECO:0007829|PDB:6M1U"
SQ SEQUENCE 562 AA; 63621 MW; 8CF655F19AF572F0 CRC64;
MALSKSMHAR NRYKDKPPDF AYLASKYPDF KQHVQINLNG RVSLNFKDPE AVRALTCTLL
REDFGLSIDI PLERLIPTVP LRLNYIHWVE DLIGHQDSDK STLRRGIDIG TGASCIYPLL
GATLNGWYFL ATEVDDMCFN YAKKNVEQNN LSDLIKVVKV PQKTLLMDAL KEESEIIYDF
CMCNPPFFAN QLEAKGVNSR NPRRPPPSSV NTGGITEIMA EGGELEFVKR IIHDSLQLKK
RLRWYSCMLG KKCSLAPLKE ELRIQGVPKV TYTEFCQGRT MRWALAWSFY DDVTVPSPPS
KRRKLEKPRK PITFVVLASV MKELSLKASP LRSETAEGIV VVTTWIEKIL TDLKVQHKRV
PCGKEEVSLF LTAIENSWIH LRRKKRERVR QLREVPRAPE DVIQALEEKK PTPKESGNSQ
ELARGPQERT PCGPALREGE AAAVEGPCPS QESLSQEENP EPTEDERSEE KGGVEVLESC
QGSSNGAQDQ EASEQFGSPV AERGKRLPGV AGQYLFKCLI NVKKEVDDAL VEMHWVEGQN
RDLMNQLCTY IRNQIFRLVA VN
