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Hum Mol Genet. 2008 Nov 1;17(21):3399-410. doi: 10.1093/hmg/ddn234. Epub 2008 Aug 8.

SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain.

Author information

  • 1Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4955, USA.

Abstract

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 alpha-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.

PMID:
18689355
[PubMed - indexed for MEDLINE]
PMCID:
PMC2566527
Free PMC Article

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