The Drosophila homologue of the hereditary spastic paraplegia protein, spastin, severs and disassembles microtubules.
Hereditary spastic paraplegias (HSPs), a group of neurodegenerative disorders characterized by lower-extremity spasticity and weakness, are most commonly caused by mutations in the spastin gene, which encodes a AAA+ ATPase related to the microtubule-severing protein katanin. A Drosophila homolog of spastin (D-spastin) was identified recently, and D-spastin RNAi-treated or genetic null flies show neurological defects, and protein overexpression decreases the density of cellular microtubules. Elucidating spastin's function and disease mechanism will require a more detailed understanding of its structure and biochemical mechanism. Here, we have investigated the effects of D-spastin, individual D-spastin domains, and D-spastin proteins bearing disease mutations on microtubules in cellular and in vitro assays. We show that D-spastin, like katanin, displays ATPase activity and uses energy from ATP hydrolysis to sever and disassemble microtubules; disease mutations abolish or partially interfere with these activities.
Roll-Mecak
Antonina
A
The Howard Hughes Medical Institute and The Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143, USA.
Vale
Ronald D
RD
D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics*; D004926:Escherichia coli; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D015151:Immunoblotting; D000074201:Katanin; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
D018076:DNA, Complementary; D029721:Drosophila Proteins; C519702:Kat60 protein, Drosophila; D049452:Green Fluorescent Proteins; D000251:Adenosine Triphosphatases; C501874:spas protein, Drosophila; D000074201:Katanin