METTL1 phospho S27

Upon tRNA-binding, the alphaC region transforms into a helix, which together with the alpha6 helix secures both ends of the tRNA variable loop (PubMed:36599985). The N-terminal disordered region is part of the catalytic pocket and essential for methyltransferase activity: upon S-adenosyl-L-methionine- and tRNA-binding, the N-terminal disordered region becomes ordered, sandwiched between the bound cofactor and the tRNA, and the WDR4 C-terminus attaches to the METTL1 N-terminus to stabilize the bound tRNA together (PubMed:36599982, PubMed:36599985). Together with WDR4, which also binds tRNAs, tRNAs undergo bending to facilitate G46 flipping into the catalytic pocket to be modified (PubMed:36599982, PubMed:36599985).

Catalytic component of METTL1-WDR4 methyltransferase complex that mediates the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031083, PubMed:31031084, PubMed:36599982, PubMed:36599985, PubMed:37369656, PubMed:37379838). Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352206, PubMed:34352207, PubMed:36599982, PubMed:36599985, PubMed:37369656). M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985). Also acts as a methyltransferase for a subset of internal N(7)-methylguanine in mRNAs (PubMed:31031084, PubMed:37379838). Internal N(7)-methylguanine methylation of mRNAs in response to stress promotes their relocalization to stress granules, thereby suppressing their translation (PubMed:31031084, PubMed:37379838). Also methylates a specific subset of miRNAs, such as let-7 (PubMed:31031083). N(7)-methylguanine methylation of let-7 miRNA promotes let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA) (PubMed:31031083). Acts as a regulator of embryonic stem cell self-renewal and differentiation (By similarity).

tRNA modification; N(7)-methylguanine-tRNA biosynthesis.

Phosphorylation at Ser-27 by PKB/AKT1 inactivates its methyltransferase activity via a steric interference mechanism in the active site that locally disrupts the catalytic center (PubMed:15861136, PubMed:36599985). Phosphorylation at Ser-27 does not affect the interaction with WDR4 (PubMed:15861136).

Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.

Ubiquitous.

• Nucleus

C12orf1, METTL1, tRNA (guanine-N(7)-)-methyltransferase, Methyltransferase-like protein 1, mRNA (guanine-N(7)-)-methyltransferase, miRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine(46)-N(7))-methyltransferase, tRNA(m7G46)-methyltransferase

• entrezGene:4234
• genbank:BC000550
• omim:604466
• swissprot:Q9UBP6

Proteins

Immunology & Infectious Disease

31471Da