Crystal structures of the human Dysferlin inner DysF domain.
BACKGROUND
Mutations 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.


RESULTS
We 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.


CONCLUSIONS
The high resolution structure of the Dysferlin DysF domain gives a template on which to interpret in detail the pathogenic mutations that lead to disease.
Altin
A
Sula
Ambrose R
AR
Cole
Corin
C
Yeats
Christine
C
Orengo
Crystallography, Biological Sciences, Institute for Structural and Molecular Biology, Birkbeck University of London, Malet Street, London WC1E 7HX, UK. n.keep@mail.cryst.bbk.ac.uk.
Nicholas H
NH
Keep
D001120:Arginine / Q000378:metabolism; D018360:Crystallography, X-Ray; D000073939:Dysferlin; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009124:Muscle Proteins / Q000737:chemistry* / Q000378:metabolism*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics; D020125:Mutation, Missense; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D014364:Tryptophan / Q000378:metabolism
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D014364:Tryptophan; D001120:Arginine