RETRACTED: The SMN structure reveals its crucial role in snRNP assembly (Retracted Article)

The spliceosome plays a fundamental role in RNA metabolism by facilitating pre-RNA splicing. To understand how this essential complex is formed, we have used protein crystallography to determine the first complete structures of the key assembler protein, SMN, and the truncated isoform, SMN Delta 7, which is found in patients with the disease spinal muscular atrophy (SMA). Comparison of the structures of SMN and SMN Delta 7 shows many similar features, including the presence of two Tudor domains, but significant differences are observed in the C-terminal domain, including 12 additional amino acid residues encoded by exon 7 in SMN compared with SMN Delta 7. Mapping of missense point mutations found in some SMA patients reveals clustering around three spatial locations, with the largest cluster found in the C-terminal domain. We propose a structural model of SMN binding with the Gemin2 protein and a heptameric Sm ring, revealing a critical assembly role of the residues 260-294, with the differences at the C-terminus of SMN Delta 7 compared with SMN likely leading to loss of small nuclear ribonucleoprotein (snRNP) assembly. The SMN complex is proposed to form a dimer driven by formation of a glycine zipper involving a helix formed by amino acid residues 263-294. These results explain how structural changes of SMN give rise to loss of SMN-mediated snRNP assembly and support the hypothesis that this loss results in atrophy of neurons in SMA.