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Spastin oligomerizes into a hexamer and the mutant spastin (E442Q) redistribute the wild‐type spastin into filamentous microtubule
Author(s) -
Pantakani D. V. Krishna,
Swapna Lakshmipuram S.,
Srinivasan Narayanaswamy,
Mannan Ashraf U.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05414.x
Subject(s) - hereditary spastic paraplegia , aaa proteins , random hexamer , mutant , microtubule , microbiology and biotechnology , biology , chemistry , biochemistry , atpase , enzyme , phenotype , gene
Spastin, a member of the ATPases associated with various cellular activities (AAA) family of proteins, is the most frequently mutated in hereditary spastic paraplegia. The defining feature of the AAA proteins is a structurally conserved AAA domain which assembles into an oligomer. By chemical cross‐linking and gel filtration chromatography, we show that spastin oligomerizes into a hexamer. Furthermore, to gain a comprehensive overview of the oligomeric structure of spastin, we generated a structural model of the AAA domain of spastin using template structure of VPS4B and p97/VCP. The generated model of spastin provided us with a framework to classify the identified missense mutations in the AAA domain from hereditary spastic paraplegia patients into different structural/functional groups. Finally, through co‐localization studies in mammalian cells, we show that E442Q mutant spastin acts in a dominant negative fashion and causes redistribution of both wild‐type spastin monomer and spastin interacting protein, RTN1 into filamentous microtubule bundles.