Dysferlin
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Dysferlin also known as dystrophy-associated fer-1-like protein is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''DYSF''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. Dysferlin is linked with
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
repair. A defect in the DYSF gene, located on chromosome 2p12-14, results in several types of
muscular dystrophy Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affe ...
; including
Miyoshi myopathy Distal myopathy is a group of rare genetic disorders that cause muscle damage and weakness, predominantly in the hands and/or feet. Mutation of many different genes can be causative. Many types involve dysferlin. Signs and symptoms All of the di ...
(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.


Structure

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 A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by th ...
(C2A-G) which are conserved across several proteins within the
ferlin family Ferlins are an ancient protein family involved in vesicle fusion and membrane trafficking. Ferlins are distinguished by their multiple tandem C2 domains, and sometimes a FerA and a DysF domain. Mutations in ferlins can cause human diseases such ...
, including dysferlin homolog
myoferlin Myoferlin is a protein that in humans is encoded by the ''MYOF'' gene. Mutations in dysferlin, a protein associated with the plasma membrane, can cause muscle weakness that affects both proximal and distal muscles. The protein encoded by this ge ...
. In fact, the C2 domain at any given position is more similar to the C2 domain at the corresponding position within other ferlin family members than the adjacent C2 domain within the same protein. This suggests that each individual C2 domain may in fact play a specific role in dysferlin function. 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, which is consistent with a growing body of evidence suggesting that the C2A domain plays a role in calcium-dependent lipid binding. 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. FerA domain is conserved among all members of ferlin protein family. There has been two single point mutations in dysferlin FerA domain that have been associated with muscular dystrophy. FerA domain is a four helix bundle and it can interact with membrane, usually in a calcium-dependent manner.


Function

The most intensively studied role for dysferlin is in a cellular process called membrane repair. Membrane repair is a critical mechanism by which cells are able to seal dramatic wounds to the plasma membrane. Muscle is thought to be particularly prone to membrane wounds given that muscle cells transmit high force and undergo cycles of contraction. Dysferlin is highly expressed in muscle, and is homologous to the ferlin family of proteins, which are thought to regulate membrane fusion across a wide variety of species and cell types. 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.


Interactions

Dysferlin has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
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.


References


Further reading

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External links


GeneReviews/NCBI/NIH/UW entry on Dysferlinopathy including Miyoshi Distal Myopathy (Miyoshi Myopathy), Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B)
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LOVD The Leiden Open Variation Database (LOVD) is a free, flexible web-based open source database developed in the Leiden University Medical Center in the Netherlands, designed to collect and display variants in the DNA sequence. The focus of an LOVD is ...
mutation database
DYSF
{{Other cell membrane proteins Proteins