methylosome

The methylosome is a multi-protein complex in eukaryotic cells that catalyzes arginine dimethylation on specific substrate proteins. The core of the complex consists of protein arginine methyltransferase 5 (PRMT5) and its cofactor MEP50 (also known as WDR77). A partner chaperone, pICln, can associate with the core to help deliver substrates to PRMT5 for methylation. The complex is primarily studied in the cytoplasm where many of its functions in snRNP biogenesis occur, though its components can be found in other cellular compartments as well.

A principal function of the methylosome is to symmetrically dimethylate arginine residues on Sm proteins (such as SmB/B', SmD1, and SmD3) and related components. This histone-independent methylation is required for the proper assembly of Sm proteins onto small nuclear RNAs to form small nuclear ribonucleoproteins (snRNPs), which are essential components of the spliceosome. PRMT5 also methylates a broader set of substrates, including certain histones, linking the methylosome to transcriptional regulation in some contexts.

Mechanistically, pICln binds nascent Sm proteins and targets them to the PRMT5-MEP50 complex for methylation. Once methylated, the Sm proteins are transferred to the SMN (survival motor neuron) complex to complete snRNP assembly. This handoff is a key step in the biogenesis of spliceosomal components and thus in pre-mRNA splicing.

The methylosome is evolutionarily conserved across eukaryotes and is regarded as an important contributor to gene expression control through its role in splicing. Dysregulation of PRMT5 or methylosome components has been linked to various cancers and developmental disorders, highlighting its biological and clinical relevance.