title: SMN complex localizes to the sarcomeric Z-disc and is a proteolytic target of calpain.
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.
authors.affiliation: Department of Genetics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4955, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walker
authors.forename: T K
authors.initials: TK
authors.lastname: Rajendra
authors.forename: Luciano
authors.initials: L
authors.lastname: Saieva
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fuentes
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Matera
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D054792:Muscle, Striated / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism*; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism; D055532:SMN Complex Proteins / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D002154:Calpain; D002118:Calcium