Human Molecular Genetics Advance Access originally published online on August 8, 2008
Human Molecular Genetics 2008 17(21):3399-3410; doi:10.1093/hmg/ddn234
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SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain
1 Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4955, USA 2 Department of Biology, Program in Molecular Biology and Biotechnology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-3280, USA 3 Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
* To whom correspondence should be addressed at: Department of Biology, University of North Carolina, 415 Fordham Hall, CB#3280, Chapel Hill, NC 27599-3280, USA. Tel: +1 9199622770; Email: agmatera{at}email.unc.edu
Received June 23, 2008; Revised July 23, 2008; Accepted August 6, 2008
Spinal muscular atrophy (SMA) is a recessive neuromuscular disease caused by mutations in the human survival motor neuron 1 (SMN1) gene. The human SMN protein is part of a large macromolecular complex involved in the biogenesis of small ribonucleoproteins. Previously, we showed that SMN is a sarcomeric protein in flies and mice. In this report, we show that the entire mouse Smn complex localizes to the sarcomeric Z-disc. Smn colocalizes with 
-actinin, a Z-disc marker protein, in both skeletal and cardiac myofibrils. Furthermore, this localization is both calcium- and calpain-dependent. Calpains are known to release proteins from various regions of the sarcomere as a part of the normal functioning of the muscle; however, this removal can be either direct or indirect. Using mammalian cell lysates, purified native SMN complexes, as well as recombinant SMN protein, we show that SMN is a direct target of calpain cleavage. Finally, myofibers from a mouse model of severe SMA, but not controls, display morphological defects that are consistent with a Z-disc deficiency. These results support the view that the SMN complex performs a muscle-specific function at the Z-discs.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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