title: In silico functional and structural characterisation of ferlin proteins by mapping disease-causing mutations and evolutionary information onto three-dimensional models of their C2 domains.
abstract: Ferlins are C2 domain proteins involved in membrane fusion events, including membrane repair and synaptic exocytosis, and their deficiency can result in muscular dystrophy and deafness. We have undertaken a structural study of their C2 domains by sequence comparison and homology modelling to understand the function of these poorly characterised proteins and to predict the molecular impact of disease-causing mutations. We observe that non-conservative mutations affecting buried residues tend to result in detrimental phenotypes, likely because of decreased protein stability, whereas most variants with replacements in surface residues do not. The few cases of exposed residues altered in variants known to cause diseases are found in conserved areas of functional importance, including essential calcium-binding regions, as deduced by analogy to other characterised C2 domains. Furthermore, we report distinct features of some C2 domains in the two known ferlin subfamilies that correlates with the presence or absence of the DysF domains. Taken altogether, our results highlight potential targets for further experimental analyses to understand the function of ferlin proteins. We believe our modelling data will aid the diagnosis of diseases associated with ferlin mutations and the development of therapeutic strategies.
authors.affiliation: Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. j_l_jimenez71@yahoo.es
authors.forename: José L
authors.initials: JL
authors.lastname: Jiménez
authors.forename: Rumaisa
authors.initials: R
authors.lastname: Bashir
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002874:Chromosome Mapping / Q000379:methods*; D003638:Deafness / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000073939:Dysferlin; D019143:Evolution, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D017386:Sequence Homology, Amino Acid
chemical_list: D002135:Calcium-Binding Proteins; C114839:DYSF protein, human; D000073939:Dysferlin; C415584:MYOF protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; C118457:OTOF protein, human