Human Molecular Genetics Advance Access originally published online on July 17, 2007
Human Molecular Genetics 2007 16(19):2349-2358; doi:10.1093/hmg/ddm192
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Targeting of SMN to Cajal bodies is mediated by self-association
1 Clinical Neurobiology, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, Exeter EX1 2LU, UK
* To whom correspondence should be addressed at: Clinical Neurobiology, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, St Luke's Campus, Exeter EX1 2LU, UK. Tel: +44 1392262939; Fax: +44 1392262926; Email: philip.young{at}pms.ac.uk
Received May 17, 2007; Accepted July 14, 2007
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.