Solution Structure of the Inner DysF Domain of Myoferlin and Implications for Limb Girdle Muscular Dystrophy Type 2B

Patel, Pryank; Harris, Richard; Geddes, Stella; Strehle, Eugen-Matthias; Watson, James D.; Bashir, Rumaisa; Bushby, K.; Driscoll, Paul C.; Keep, Nicholas H.

doi:10.1016/j.jmb.2008.04.046

Cited by 34 publications

(58 citation statements)

References 60 publications

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“…We show that mutations recorded in UMD-DYSF affect 3.3% of all amino acids residing outside annotated domains and 5.0% of all amino acids residing within domains. In particular, we confirm the susceptibility of the repeated DysF domain to mutations (Patel, et al, 2008) as the UMD-DYSF mutations affect 7.9% of the amino acids within this domain. The "Structure" function summarizes the distribution of small rearrangements in structural domains and in possible calcium binding residues of the dysferlin protein.…”

Section: Exonic Variantssupporting

confidence: 67%

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

et al. 2011

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Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. As a step towards a better understanding of the DYSF mutational spectrum, and towards possible inclusion of patients in future therapeutic clinical trials, we set up the Universal Mutation Database for Dysferlin (UMD-DYSF), a Locus-Specific Database developed with the UMD® software. The main objective of UMD-DYSF is to provide an updated compilation of mutational data and relevant interactive tools for the analysis of DYSF sequence variants, for diagnostic and research purposes. In particular, specific algorithms can facilitate the interpretation of newly identified intronic, missense-or isosemantic-exonic sequence variants, a problem encountered recurrently during genetic diagnosis in dysferlinopathies. UMD-DYSF v1.0 is freely accessible at www.umd.be/DYSF/. It contains a total of 742 mutational entries corresponding to 266 different disease-causing mutations identified in 558 patients worldwide diagnosed with dysferlinopathy. This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF diseasecausing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD-DYSF.

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Section: Exonic Variantssupporting

confidence: 67%

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

et al. 2011

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“…Ferlin C2 domains share stronger similarity to positionally equivalent domains in other ferlin family members than to C2 domains within the same molecule (6). Myoferlin, Fer1L5, and dysferlin are unique from the other ferlin family members in that they also contain a DysF domain present in the ferlins that is the hypothesized binding site for caveolin-3 (31). The DysF domain is also found in the human ␤-propeller protein DKFZP434B0335 and the yeast peroxisomal proteins Pex30p and Pex31p (31).…”

Section: Fer1l5 Is Related To Dysferlin and Myoferlin-the Fer1l5mentioning

confidence: 99%

“…Myoferlin, Fer1L5, and dysferlin are unique from the other ferlin family members in that they also contain a DysF domain present in the ferlins that is the hypothesized binding site for caveolin-3 (31). The DysF domain is also found in the human ␤-propeller protein DKFZP434B0335 and the yeast peroxisomal proteins Pex30p and Pex31p (31). A seventh C2 domain can be identified between C2D and C2E in dysferlin and myoferlin by the SMART algorithm and other protein prediction programs (29,32); however, this domain is highly divergent from the standard C2 domain profile.…”

Section: Fer1l5 Is Related To Dysferlin and Myoferlin-the Fer1l5mentioning

confidence: 99%

Endocytic Recycling Proteins EHD1 and EHD2 Interact with Fer-1-like-5 (Fer1L5) and Mediate Myoblast Fusion

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Pytel²,

Gardikiotes³

et al. 2011

Journal of Biological Chemistry

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The mammalian ferlins are calcium-sensing, C2 domaincontaining proteins involved in vesicle trafficking. Myoferlin and dysferlin regulate myoblast fusion and muscle membrane resealing, respectively. Correspondingly, myoferlin is most highly expressed in singly nucleated myoblasts, whereas dysferlin expression is increased in mature, multinucleated myotubes. Myoferlin also mediates endocytic recycling and participates in trafficking the insulin-like growth factor receptor. We have now characterized a novel member of the ferlin family, Fer1L5, because of its high homology to dysferlin and myoferlin. We found that Fer1L5 protein is expressed in small myotubes that contain only two to four nuclei. We also found that Fer1L5 protein binds directly to the endocytic recycling proteins EHD1 and EHD2 and that the second C2 domain in Fer1L5 mediates this interaction. Reduction of EHD1 and/or EHD2 inhibits myoblast fusion, and EHD2 is required for normal translocation of Fer1L5 to the plasma membrane. The characterization of Fer1L5 and its interaction with EHD1 and EHD2 underscores the complex requirement of ferlin proteins and mediators of endocytic recycling for membrane trafficking events during myotube formation.

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“…The human myoferlin (dysferlin paralogue) inner DysF domain structure was solved by Nuclear Magenetic Resonance (NMR) and showed a novel fold. This consists of two long beta strands connected by a long loop that caps the sheet edges in certain sections [18]. The structure contains arginine/tryptophan stacks that holds the fold together and are largely conserved throughout DysF domain sequences (Figure 1b).…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of the human Dysferlin inner DysF domain

et al. 2014

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BackgroundMutations in dysferlin, the first protein linked with the cell membrane repair mechanism, causes a group of muscular dystrophies called dysferlinopathies. Dysferlin is a type two-anchored membrane protein, with a single C terminal trans-membrane helix, and most of the protein lying in cytoplasm. Dysferlin contains several C2 domains and two DysF domains which are nested one inside the other. Many pathogenic point mutations fall in the DysF domain region.ResultsWe describe the crystal structure of the human dysferlin inner DysF domain with a resolution of 1.9 Ångstroms. Most of the pathogenic mutations are part of aromatic/arginine stacks that hold the domain in a folded conformation. The high resolution of the structure show that these interactions are a mixture of parallel ring/guanadinium stacking, perpendicular H bond stacking and aliphatic chain packing.ConclusionsThe high resolution structure of the Dysferlin DysF domain gives a template on which to interpret in detail the pathogenic mutations that lead to disease.

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Solution Structure of the Inner DysF Domain of Myoferlin and Implications for Limb Girdle Muscular Dystrophy Type 2B

Cited by 34 publications

References 60 publications

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

Endocytic Recycling Proteins EHD1 and EHD2 Interact with Fer-1-like-5 (Fer1L5) and Mediate Myoblast Fusion

Crystal structures of the human Dysferlin inner DysF domain

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