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Protein encoded by the DYSF gene in humans

Dysferlin also known as dystrophy associated fer 1 like protein is a protein that in humans is encoded by the DYSF gene. Dysferlin is linked with plasma membrane repair., stabilization of calcium signaling and the development of the T tubule system of the muscle A defect in the DYSF gene, located on chromosome 2p12 14, results in several types of muscular dystrophy; including Miyoshi myopathy (MM), Limb girdle muscular dystrophy type 2B (LGMD2B) and Distal Myopathy (DM). A reduction or absence of dysferlin, termed dysferlinopathy, usually becomes apparent in the third or fourth decade of life and is characterised by weakness and wasting of various voluntary skeletal muscles. Pathogenic mutations leading to dysferlinopathy can occur throughout the DYSF gene.

The human dysferlin protein is a 237 kilodalton type II transmembrane protein. It contains a large intracellular cytoplasmic N terminal domain, an extreme C terminal transmembrane domain, and a short C terminal extracellular domain. The cytosolic domain of dysferlin is composed of seven highly conserved C2 domains (C2A G) which are conserved across several proteins within the ferlin family, including dysferlin homolog myoferlin. Mutations in each of these domains can cause dysferlinopathy. A crystal structure of the C2A domain of human dysferlin has been solved, and reveals that the C2A domain changes conformation when interacting with calcium ions, Its ability to stabilize calcium signaling in the intact dysferlin protein depends on its calcium binding activity. In addition to the C2 domains, dysferlin also contains "FerA" and "DysF" domains. Mutations in both FerA and DysF can cause muscular dystrophies. DysF domain has an interesting structure as in contains one DysF domain within another DysF domain, a result of gene duplication; however, the function of this domain is currently unknown. Several lines of evidence suggest that dysferlin may be involved in membrane repair in muscle. First, dysferlin deficient muscle fibers show accumulation of vesicles (which are critical for membrane repair in non muscle cell types) near membrane lesions, indicating that dysferlin may be required for fusion of repair vesicles with the plasma membrane. Further, dysferlin deficient muscle fibers take up extracellular dyes to a greater extent than wild type muscle fibers following laser induced wounding in vitro. Dysferlin is also markedly enriched at membrane lesions with several additional proteins thought to be involved in membrane resealing, including annexin and MG53. Exactly how dysferlin contributes to membrane resealing is not clear, but biochemical evidence indicates that dysferlin may bind lipids in a calcium dependent manner, consistent with a role for dysferlin in regulating fusion of repair vesicles with the sarcolemma during membrane repair. Furthermore, live cell imaging of dysferlin eGFP expressing myotubes indicates that dysferlin localizes to a cellular compartment that responds to injury by forming large dysferlin containing vesicles, and formation of these vesicles may contribute to wound repair. Dysferlin may also be involved in Alzheimer's disease pathogenesis. Another well studied role for dysferlin is in stabilization of calcium signaling, especially following a mild injury. This approach was based on two observations: that muscle lacking dysferlin that is injured by eccentric contractions can repair its plasma membrane, or sarcolemma, as efficiently as healthy muscle can, and that most of the dysferlin in healthy muscle is concentrated in the transverse tubules at triad junctions, where calcium release is regulated. Destabilization of signaling in dysferlinopathic muscle can result in the generation of calcium waves, which can contribute to the disease pathology. Nearly every change in dysferlin that affects membrane repair also destabilizes calcium signaling, suggesting that these two activities are closely linked. Remarkably, however, membrane repair requires calcium ions, whereas calcium ions contribute to the destabilization of signaling when dysferlin is absent or mutated. These paradoxical results have yet to be reconciled.

Dysferlin has been shown to bind to itself, to form dimers and perhaps larger oligomers. It can also has been shown to interact with Caveolin 3 in skeletal muscle, and this interaction is thought to retain dysferlin within the plasma membrane. Dysferlin also interacts with MG53, and a functional interaction between dysferlin, caveolin 3 and MG53 is thought to be critical for membrane repair in skeletal muscle.