Human Molecular Genetics Advance Access published online on August 8, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn234
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The 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 2 Department of Biology, Program in Molecular Biology & Biotechnology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-3280 3 Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
Address correspondence to: A. Gregory Matera, Department of Biology, University of North Carolina, 415 Fordham Hall, CB#3280, Chapel Hill, NC 27599-3280, Tel: (919) 962-2770, e-mail: 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 Neurons 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 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.
* These authors contributed equally to this work.
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