Key result
In Drosophila, the nebulin family member Lasp localizes to the Z-disc edges and A-band to regulate thin filament length, I-band architecture, and filament spacing using just two nebulin repeats.
Lasp regulates thin filament length and I-band architecture in Drosophila, establishing it as a model for understanding nebulin repeat function relevant to nemaline myopathy.
No immediate clinical implications; hypothesis-generating for nebulin-related myopathies and requires mammalian validation.
Mutations in nebulin, a giant muscle protein with 185 actin-binding nebulin repeats, are the major cause of nemaline myopathy in humans. Nebulin sets actin thin filament length in sarcomeres, potentially by stabilizing thin filaments in the I-band, where nebulin and thin filaments coalign. However, the precise role of nebulin in setting thin filament length and its other functions in regulating power output are unknown. Here, we show that Lasp, the only member of the nebulin family in Drosophila melanogaster, acts at two distinct sites in the sarcomere and controls thin filament length with just two nebulin repeats. We found that Lasp localizes to the Z-disc edges to control I-band architecture and also localizes at the A-band, where it interacts with both actin and myosin to set proper filament spacing. Furthermore, introducing a single amino acid change into the two nebulin repeats of Lasp demonstrated different roles for each domain and established Lasp as a suitable system for studying nebulin repeat function.
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Fernandes et al. (2014) studied Nemaline myopathy model (muscle architecture). Lasp genetic mutations and transgenes vs. Wild-type Drosophila was evaluated on Sarcomere length, thin filament length, and flight ability. In Drosophila, the nebulin family member Lasp localizes to the Z-disc edges and A-band to regulate thin filament length, I-band architecture, and filament spacing using just two nebulin repeats.
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