Calpain cleavage within dysferlin exon 40a releases a synaptotagmin-like module for membrane repair.
Bottom Line: Here we show that injury-activated cleavage of dysferlin is mediated by the ubiquitous calpains via a cleavage motif encoded by alternately spliced exon 40a.Of importance, we reveal that myoferlin and otoferlin are also cleaved enzymatically to release similar C-terminal modules, bearing two C2 domains and a transmembrane domain.Evolutionary preservation of this feature highlights its functional importance and suggests that this highly conserved C-terminal region of ferlins represents a functionally specialized vesicle fusion module.
Affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.Show MeSH
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Mentions: In this study, we aimed to identify the mechanisms controlling the injury-activated cleavage of dysferlin and the release of the mini-dysferlinC72 synaptotagmin-like module. Molecular weight calculations of mini-dysferlinC72 (72 kDa) predict that the cleavage site lies between exons 40 and 41, between C2DE and C2E within the dysferlin protein domain structure (Figure 1, A and B). An alternatively spliced exon, exon 40a, occurs between exons 40 and 41. In silico analysis of human dysferlin exon 40a (Liu et al., 2011; ccd.biocuckoo.org), together with a number of dysferlin orthologues, revealed the presence of a putative calpain cleavage site within this alternatively spliced exon, with the highest likelihood of cleavage occurring at the LAPTNTA–SPPSSPH junction in each case (Figure 1C).
Affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Sydney, NSW 2145, Australia Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Sydney, Australia.