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Ferlin proteins have been implicated
in membrane fusion events.
Fusion is essential for muscle repair and regeneration. Single cell myoblasts fuse to form
multinucleate syncytial myotubes.
Upon injury, resealing of membrane tears must occur in mature skeletal
muscle myotubes. Dysferlin was
first discovered as the gene mutated in Limb Girdle Muscular Dystrophy, type
2B and in Myoshi Myopathy.
Dysferlin is highly related to myoferlin as they are both
transmembrane proteins with multiple C2 domains. C2 domains have been implicated in membrane fusion events
in other systems, such as the membrane fusion that occurs during exocytosis
at nerve terminals.
We characterized myoferlin and found that it is highly
expressed in fusing myotubes. We
also found that the first C2 domain of both myoferlin and dysferlin binds
phospholipids in a calcium-sensitive manner. A mutation in dysferlin that is associated with muscular
dystrophy was found to disrupt calcium-sensitive phospholipid binding. We are interested in understanding
more about membrane fusion events in muscle and specifically the role of
dysferlin and myoferlin.
References:
Davis,
D. B., A. Delmonte, C. T. Ly and E. M. McNally. Myoferlin, a candidate gene and potential modifier of
muscular dystrophy. (2000) Hum.
Mol. Gen. 9:217-226.
Vainzof,
M., L. V.B. Anderson, E. M. McNally, D. B. Davis, G. Faulkner, E. S. Moreira,
R. C. M. Pavanello, M. R. Passos-Bueno and M. Zatz. Dysferlin protein analysis in the muscular dystrophies.
(2001) J. Mol. Neurosci. 1:71-80.
Belt
Davis, D., K. R. Doherty, A. Delmonte and E. M. McNally. Calcium-sensitive phospholipid
binding properties of normal and mutant ferlin C2 domains. (2002) J. Biol. Chem.
277:22883-22888.
Doherty,
K. R. and E. M. McNally.
Repairing the tears: dysferlin in muscle membrane repair. (2003) Trends Mol. Med. 8:327-30.
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