Decoding Protein-Methylating METTLs in Humans: Structural, Functional, and Disease Insights over the Past Decade

Methylation of proteins is a critical post-translational modification that regulates diverse cellular processes, including signal transduction, protein stability, and enzymatic activity. The methyltransferase enzymes that catalyse the addition of such methyl groups onto target molecules fall into a wide variety of categories and as such are classified into numerous families. Among them, the methyltransferase-like (METTL) family represents a unique cluster of enzymes with structural similarity to arginine methyltransferases. This family comprises 27 members, many of which methylate lysine residues on proteins, while others target various forms of RNA. Although discovered just over a decade ago, the protein-methylating METTLs remain incompletely characterised. Notably, most identified protein substrates are non-histone proteins, underscoring the distinctive functional roles of these enzymes. This review focuses exclusively on the protein-methylating METTL family members, summarising current knowledge of their structural features, enzymatic targets, sub-cellular localisation, and expression patterns. Their emerging relevance to disease, particularly cancer, is also highlighted, alongside areas where mechanistic understanding remains limited. By consolidating recent advances, this review aims to provide a comprehensive overview of protein-methylating METTLs in humans and to identify the critical knowledge gaps that will guide future research into their biological roles and therapeutic potential.