Arginine residues in RG-rich proteins are frequently dimethylated 
posttranslationally by protein arginine methyltransferases (PRMTs). The most 
common methylation pattern is asymmetrical dimethylation, a modification 
important for protein shuttling and signal transduction. Symmetrically 
dimethylated arginines (sDMA) have until now been confined to the myelin basic 
protein MBP and the Sm proteins D1 and D3. We show here by mass spectrometry and 
protein sequencing that also the human Sm protein B/B' and, for the first time, 
one of the Sm-like proteins, LSm4, contain sDMA in vivo. The symmetrical 
dimethylation of B/B', LSm4, D1, and D3 decisively influences their binding to 
the Tudor domain of the "survival of motor neurons" protein (SMN): inhibition of 
dimethylation by S-adenosylhomocysteine (SAH) abolished the binding of D1, D3, 
B/B', and LSm4 to this domain. A synthetic peptide containing nine sDMA-glycine 
dipeptides, but not asymmetrically modified or nonmodified peptides, 
specifically inhibited the interaction of D1, D3, B/B', LSm4, and UsnRNPs with 
SMN-Tudor. Recombinant D1 and a synthetic peptide could be methylated in vitro 
by both HeLa cytosolic S100 extract and nuclear extract; however, only the 
cytosolic extract produced symmetrical dimethylarginines. Thus, the Sm-modifying 
PRMT is cytoplasmic, and symmetrical dimethylation of B/B', D1, and D3 is a 
prerequisite for the SMN-dependent cytoplasmic core-UsnRNP assembly. Our 
demonstration of sDMAs in LSm4 suggests additional functions of sDMAs in 
tri-UsnRNP biogenesis and mRNA decay. Our findings also have interesting 
implications for the understanding of the aetiology of spinal muscular atrophy 
(SMA).