METTL1

METTL1, or methyltransferase-like 1, is a conserved eukaryotic enzyme that functions as part of a protein complex to modify RNA. In humans, METTL1 forms a functional heterodimer with WDR4 (WD repeat-containing protein 4), and this METTL1–WDR4 complex acts as a tRNA m7G methyltransferase. The primary catalytic activity of the complex is the N7-methylguanosine (m7G) modification at position 46 of transfer RNA (tRNA), a modification that helps stabilize tRNA structure and influence translation. The reaction consumes S-adenosyl-L-methionine (SAM) as the methyl donor.

Substrates and specificity of METTL1 are best established for tRNA, where m7G46 modification is common across many cytoplasmic tRNAs. In addition to tRNA, some studies have reported activity on other RNA species in certain contexts, but tRNA is the canonical substrate. The m7G46 modification is thought to affect tRNA folding, processing, and decoding efficiency, thereby impacting overall protein synthesis and cellular growth.

Biochemically, METTL1 belongs to the family of SAM-dependent methyltransferases and contains a conserved catalytic domain typical of these enzymes. WDR4 provides essential structural support and substrate recognition, enabling proper positioning of the tRNA substrate within the active site. Structural and biochemical analyses have shown that the METTL1–WDR4 interface is critical for catalytic activity and substrate binding; the complex is conserved from yeast to humans.

Physiologically, METTL1 is widely expressed and participates in normal development and cellular homeostasis. Dysregulation of METTL1 expression or function has been linked to altered RNA modification patterns and has been observed in various cancers, highlighting its potential role in controlling translation and cell proliferation. Ongoing research aims to define the full spectrum of METTL1’s RNA substrates and its implications in health and disease.