User:Isabela de Aquino Zogbi/Sandbox1
From Proteopedia
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Introduction
Dysferlin is a large transmembrane protein of approximately 230kDa encoded by the dysferlin gene (DYSF omim) highly expressed in striated skeletal and cardiac muscle, but can be found in kidney, placenta, lung and brain tissues (3). Dysferlin is a protein that belongs to the same family of genes as Caenorhabditis elegans ferlin, also known as ferlin-like proteins, therefore the name it was given, and can also known as ferlin 1-like 1. It is common to this family the presence of type II transmembrane domains, where the most part of the protein faces de cytoplasm (3). This protein is critical for repair of muscle membranes after damage and its mutation lead to a progressive muscle dystrophy, since in its absence the membrane tear is not adequately repaired leading to myofiber necrosis and gradual and progressive loss of muscle tissue (1;5). The protein rapidly responds to injury with a Ca2+ influx mechanism which aids the repair. Dysferlin-deficient muscle fibers demonstrate a primary defect in Ca2+-dependent, vesicle-mediated membrane repair (5).
Structure and Function
Dysferlin has seven tandem C2 domains (C2A, B, D, E and G), three Fer domains (FerA, FerB and FerI) which are short conserved regions found only in the ferlin protein family and are not yet shown to be folded domains (2), two Dysf domains and a C-terminal transmembrane domain. C2 domains are calcium sensitive phospholipid binding domains with an approximate length of 130 amino acids (5), while the function of the Dysf domain remains unclear (1;2). Dysferlin also has a single C-terminal transmembrane helix embedded in a patching vesicle. The presence of the C2 domains is common to ferlin-like proteins, in which only the C2A domain binds strongly to lipids in a calcium dependent way. The other domains have weaker bonds or are calcium independent. Also, C2A, E and F domains have shown a relevant function in the protein activity (5). Many dysferlinopathy causing mutations fall in the DysF domains (2). One Dysf domain is inserted into the other Dysf domain forming an inner Dysf domain and a two part outer Dysf domain. The Dysf domain is held together by arginine/ aromatic sidechain stacking. Dysferlin function is linked with calcium-activated membrane repair caused by fusing aggregated intracellular vesicles with the sarcolemma at the site of injury(2).
It has been shown that dysferlin deficiency delays myoblast (undifferentiated mononuclear muscle cells) fusion/maturation in vitro, suggesting that dysferlin may also participate in muscle differentiation and regeneration process (3).
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Structural highlights
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