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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calpain / metabolism*
  • Disease Models, Animal
  • Mice
  • Mice, Inbred C57BL
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • Muscle, Striated / metabolism
  • Muscular Atrophy, Spinal / genetics*
  • Muscular Atrophy, Spinal / metabolism*
  • Ribonucleoproteins, Small Nuclear / metabolism
  • SMN Complex Proteins / metabolism*
  • Sarcomeres / metabolism*
  • Survival of Motor Neuron 1 Protein / metabolism

Substances

  • Muscle Proteins
  • Ribonucleoproteins, Small Nuclear
  • SMN Complex Proteins
  • Survival of Motor Neuron 1 Protein
  • Calpain
  • Calcium