Human Molecular Genetics Advance Access published online on December 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi447
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1 The Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown St., Liverpool L69 3BX, UK
* To whom correspondence should be addressed. The pure hereditary spastic paraplegias (HSPs) are a group of conditions in which there is progressive length-dependent degeneration of the distal ends of the corticospinal tract axons, resulting in spastic paralysis of the legs. Pure HSPs are most frequently inherited in an autosomal dominant pattern and are commonly caused by mutations in either the SPG4 gene spastin or in the SPG3A gene atlastin. To identify binding partners for spastin, we carried out a yeast two-hybrid screen on a brain cDNA library, using spastin as bait. Remarkably, nearly all of the positive interacting prey clones coded for atlastin. We have verified the physiological relevance of this interaction using co-immunoprecipitation, GST-pull down and intracellular co-localisation experiments. We show that the spastin domain required for binding to atlastin lies within the N-terminal 80 residues of the protein, a region that is only present in the predominantly cytoplasmic full-length spastin isoform. These data suggest that spastin and atlastin function in the same biochemical pathway and that it is the cytoplasmic function of spastin which is important for the pathogenesis of HSP. They also provide further evidence for a physiological and pathological role for spastin in membrane dynamics.
Received June 6, 2005
Revised November 23, 2005
Accepted December 1, 2005
Article
Spastin and atlastin, two proteins mutated in autosomal dominant hereditary spastic paraplegia, are binding partners
Christopher M. Sanderson 1,
James W. Connell 2,
Thomas L. Edwards 2,
Nicholas A. Bright 3,
Simon Duley 4,
Amanda Thompson 4,
J. Paul Luzio 3,
and
Evan Reid 5 *
2 Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge CB2 2XY, UK
3 Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Cambridge CB2 2XY, UK
4 Medical Research Council Rosalind Franklin Centre for Genomics Research, Hinxton, Cambridge, CB10 1SB, UK
5 Cambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom
Evan Reid, E-mail: ealr4{at}cam.ac.uk
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