{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"Q86W50","secondaryAccessions":["D3DTI8","Q86TE5","Q96T16","Q9BVG7"],"uniProtkbId":"MET16_HUMAN","entryAudit":{"firstPublicDate":"2007-11-13","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2009-11-24","entryVersion":156,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"RNA N(6)-adenosine-methyltransferase METTL16"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197299"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33428944"}],"value":"2.1.1.348"}]},"alternativeNames":[{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.16"}],"value":"Methyltransferase 10 domain-containing protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"27872311"}],"value":"Methyltransferase-like protein 16"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"U6 small nuclear RNA (adenine-(43)-N(6))-methyltransferase"},"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29051200"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32266935"}],"value":"2.1.1.346"}]}]},"genes":[{"geneName":{"evidences":[{"evidenceCode":"ECO:0000303","source":"PubMed","id":"27872311"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:28484"}],"value":"METTL16"},"synonyms":[{"evidences":[{"evidenceCode":"ECO:0000303","source":"Reference","id":"Ref.16"},{"evidenceCode":"ECO:0000312","source":"HGNC","id":"HGNC:28484"}],"value":"METT10D"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27872311"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29051200"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197299"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32266935"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33428944"}],"value":"RNA N6-methyltransferase that methylates adenosine residues at the N(6) position of a subset of RNAs and is involved in S-adenosyl-L-methionine homeostasis by regulating expression of MAT2A transcripts (PubMed:28525753, PubMed:30197297, PubMed:30197299, PubMed:33428944, PubMed:33930289). Able to N6-methylate a subset of mRNAs and U6 small nuclear RNAs (U6 snRNAs) (PubMed:28525753). In contrast to the METTL3-METTL14 heterodimer, only able to methylate a limited number of RNAs: requires both a 5'UACAGAGAA-3' nonamer sequence and a specific RNA structure (PubMed:28525753, PubMed:30197297, PubMed:30197299). Plays a key role in S-adenosyl-L-methionine homeostasis by mediating N6-methylation of MAT2A mRNAs, altering splicing of MAT2A transcripts: in presence of S-adenosyl-L-methionine, binds the 3'-UTR region of MAT2A mRNA and specifically N6-methylates the first hairpin of MAT2A mRNA, preventing recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production of S-adenosylmethionine synthase (PubMed:28525753, PubMed:33930289). In S-adenosyl-L-methionine-limiting conditions, binds the 3'-UTR region of MAT2A mRNA but stalls due to the lack of a methyl donor, preventing N6-methylation and promoting expression of MAT2A (PubMed:28525753). In addition to mRNAs, also able to mediate N6-methylation of U6 small nuclear RNA (U6 snRNA): specifically N6-methylates adenine in position 43 of U6 snRNAs (PubMed:28525753, PubMed:29051200, PubMed:32266935). Also able to bind various lncRNAs, such as 7SK snRNA (7SK RNA) or 7SL RNA (PubMed:29051200). Specifically binds the 3'-end of the MALAT1 long non-coding RNA (PubMed:27872311)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"adenosine in U6 snRNA + S-adenosyl-L-methionine = N(6)-methyladenosine in U6 snRNA + S-adenosyl-L-homocysteine + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:52808"},{"database":"Rhea","id":"RHEA-COMP:13573"},{"database":"Rhea","id":"RHEA-COMP:13574"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:57856"},{"database":"ChEBI","id":"CHEBI:59789"},{"database":"ChEBI","id":"CHEBI:74411"},{"database":"ChEBI","id":"CHEBI:74449"}],"ecNumber":"2.1.1.346","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29051200"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32266935"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:52809"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29051200"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32266935"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"an adenosine in mRNA + S-adenosyl-L-methionine = an N(6)-methyladenosine in mRNA + S-adenosyl-L-homocysteine + H(+)","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:55584"},{"database":"Rhea","id":"RHEA-COMP:12414"},{"database":"Rhea","id":"RHEA-COMP:12417"},{"database":"ChEBI","id":"CHEBI:15378"},{"database":"ChEBI","id":"CHEBI:57856"},{"database":"ChEBI","id":"CHEBI:59789"},{"database":"ChEBI","id":"CHEBI:74411"},{"database":"ChEBI","id":"CHEBI:74449"}],"ecNumber":"2.1.1.348","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197299"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33428944"}]},"physiologicalReactions":[{"directionType":"left-to-right","reactionCrossReference":{"database":"Rhea","id":"RHEA:55585"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197299"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33428944"}]}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33428944"}],"value":"Methyltransferase activity is autoinhibited by the K-loop region that blocks S-adenosyl-L-methionine-binding (PubMed:30197297). Upon activation, K-loop changes conformation, allowing S-adenosyl-L-methionine-binding and subsequent methyltransferase activity (PubMed:30197297). mRNA N6-adenosine-methyltransferase activity is inhibited by zinc (PubMed:33428944)"}],"commentType":"ACTIVITY REGULATION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29051200"}],"value":"Interacts with MEPCE (PubMed:29051200). Interacts with LARP7 (PubMed:29051200)"}],"commentType":"SUBUNIT"},{"commentType":"SUBCELLULAR LOCATION","subcellularLocations":[{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"27872311"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31940410"}],"value":"Nucleus","id":"SL-0191"}},{"location":{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31940410"}],"value":"Cytoplasm","id":"SL-0086"}}]},{"commentType":"ALTERNATIVE PRODUCTS","events":["Alternative splicing"],"isoforms":[{"name":{"value":"1"},"isoformIds":["Q86W50-1"],"isoformSequenceStatus":"Displayed"},{"name":{"value":"2"},"isoformIds":["Q86W50-2"],"sequenceIds":["VSP_029340","VSP_029341"],"isoformSequenceStatus":"Described"}]},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"28525753"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"32266935"}],"value":"The VCR (vertebrate conserved) regions bind the first hairpin of MAT2A mRNAs (PubMed:28525753). The VCR regions interact with the internal stem-loop within U6 snRNAs, inducing the conformational rearrangement of the A43-containing region of U6 snRNA, thereby modifying the RNA structure to become suitable for productive catalysis by the methyltransferase region (PubMed:32266935)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"}],"value":"The K-loop region occludes the S-adenosyl-L-methionine-binding pocket (PubMed:30197297). Upon activation, conformation of the K-loop changes, allowing S-adenosyl-L-methionine-binding (PubMed:30197297)"}],"commentType":"DOMAIN"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"Belongs to the methyltransferase superfamily. METTL16/RlmF family"}],"commentType":"SIMILARITY"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000250","source":"UniProtKB","id":"Q9CQG2"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"33930289"}],"value":"According to a report, N6-methylation of MAT2A affects MAT2A mRNA stability instead of preventing splicing (By similarity). However, it was later shown that N6-methylation of MAT2A transcripts prevents recognition of their 3'-splice site by U2AF1/U2AF35, thereby inhibiting splicing and protein production (PubMed:33930289)"}],"commentType":"CAUTION"},{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29593291"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197297"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30197299"}],"value":"Stoichiometry of the protein is unclear. According to two reports, the methyltransferase acts as a monomer (PubMed:30197297, PubMed:30197299). According to a another paper, it acts as a homodimer (PubMed:29593291)"}],"commentType":"CAUTION"},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Erroneous termination","sequence":"BAB55094.1","note":"Truncated C-terminus.","evidences":[{"evidenceCode":"ECO:0000305"}]},{"commentType":"SEQUENCE CAUTION","sequenceCautionType":"Frameshift","sequence":"CAD89999.2","evidences":[{"evidenceCode":"ECO:0000305"}]}],"features":[{"type":"Chain","location":{"start":{"value":1,"modifier":"EXACT"},"end":{"value":562,"modifier":"EXACT"}},"description":"RNA N(6)-adenosine-methyltransferase 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