The survival of motor neurons protein: Interactions and functional implications for ribonucleoprotein biogenesis

Spinal Muscular Atrophy (SMA) is an often lethal autosomal recessive neurodegenerative disease that targets alpha motor neurons of the spinal cord. The survival of motor neurons (SMN) gene, the SMA-determining gene, is deleted or mutated in SMA patients. The SMN protein is part of a macromolecular complex which includes Gemin2, the DEAD box protein Gemin3, Gemin4, the WD repeat protein Gemin5, and now two novel components, Gemin6 and Gemin7, which we characterize here. The SMN complex functions in the biogenesis of spliceosomal snRNPs (small nuclear ribonucleoproteins) and likely other ribonucleoprotein particles, transcription and pre-mRNA splicing. SMN interacts with a variety of arginine- and glycine-rich substrates, including Sm and Lsm proteins, RNA helicase A, and hnRNPU. Here we demonstrate that the proteins fibrillarin and GAR1, markers of the snoRNPs (small nucleolar ribonucleoproteins) involved in pre-ribosomal RNA processing, interact with SMN. The domains of SMN necessary for these interactions, as well as for the association of SMN with its other interacting proteins and the Gemins, are defined, particularly emphasizing the role of the amino terminal domains of SMN in these interactions. Fibrillarin, GAR1 and all of the other SMN interacting proteins are components of RNP complexes, suggesting that the SMN complex functions as a master assembler of RNPs. The best-characterized role of the SMN complex has been in snRNP biogenesis. SMN directly interacts with both the UsnRNA and the Sm proteins to mediate snRNP assembly. Interestingly, the symmetric dimethylation of the Sm proteins is necessary for their interaction with SMN. This post-translational modification that converts arginines to dimethyl-arginines is performed by a macromolecular complex termed the methylosome, which contains the proteins MEP50, pICln and the arginine methyltransferase JBP1. Here, we analyzed the role of Gemin6 and of the methylosome in snRNP assembly. Further analysis of the functions of the SMN complex will hopefully lead to an understanding of the functional defects that cause motor neuron degeneration