Targeting of SMN to Cajal bodies is mediated by self-association

• Published in: Human molecular genetics 2007-10, Vol.16 (19), p.2349-2358
• Main Authors: Morse, Robert, Shaw, Debra J., Todd, Adrian G., Young, Philip J.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Biological and medical sciences; Coiled Bodies - genetics; Coiled Bodies - metabolism; Coiled Bodies - pathology; Cyclic AMP Response Element-Binding Protein - chemistry; Cyclic AMP Response Element-Binding Protein - genetics; Cyclic AMP Response Element-Binding Protein - metabolism; Exons - genetics; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; HeLa Cells; Humans; Immunohistochemistry; Molecular and cellular biology; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Structure, Tertiary; Protein Transport; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; SMN Complex Proteins; Tumor Cells, Cultured
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm192

The childhood autosomal recessive disorder spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron (SMN) gene. SMN localizes diffusely in the cytoplasm and in distinct nuclear structures called Cajal bodies. Cajal bodies are believed to be the storage and processing sites of several ribonucleoproteins. Here, using a novel panel of SMN exon deletion constructs, we report a systematic analysis of internal targeting domains in the SMN protein. We demonstrate that the peptides encoded by exons 2b, 3 and 6 perform an integral role in the cellular targeting of SMN. In addition, we identify a nine amino acid motif within the highly conserved sequences of the exon 2b encoded domain that mediates Cajal body targeting and self-association. Deletion of this domain dramatically affects SMN activity and results in a dominant-negative clone. These results identify critical domains within the SMN protein and have an impact on our understanding of the SMN protein with regards to SMA as well as cellular biology.