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 t...

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Bibliographic Details
Published in:	Journal of the neurological sciences 2007-09, Vol.260 (1), p.114-123
Main Authors:	Jiménez, José L, Bashir, Rumaisa
Format:	Article
Language:	eng
Subjects:	Animals Biological and medical sciences C2 domain Calcium-Binding Proteins Chromosome Mapping - methods Deafness - genetics Deafness - metabolism Deafness - physiopathology Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Dysferlin Evolution, Molecular Evolutionary analysis Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy Humans Medical sciences Membrane Proteins - chemistry Membrane Proteins - genetics Models, Molecular Molecular Sequence Data Muscle Proteins - chemistry Muscle Proteins - genetics Muscular Dystrophies - genetics Muscular Dystrophies - metabolism Muscular Dystrophies - physiopathology Muscular dystrophy Mutation - genetics Nervous system (semeiology, syndromes) Neurology Otoferlin Protein Structure, Tertiary - genetics Proteomics - methods Sequence Homology, Amino Acid Structural modelling
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Summary:	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.
ISSN:	0022-510X 1878-5883