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A mutation in torsinA, an AAA ATPase protein, causes DYT1 dystonia in humans. On page 855, Goodchild and Dauer identify two protein binding partners of torsinA, one that localizes to the ER membrane and one that spans the inner membrane of the nuclear envelope. The team hypothesizes that DYT1 is a nuclear envelope disease, and that identification of such protein complexes will provide a mechanistic probe into a poorly characterized region of the cell.
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3 p; a7 b. `+ [' `/ s3 s5 KIn wild-type cells, the majority of torsinA protein localizes to the lumen of the ER, while a small proportion associates with the nuclear envelope. In cells carrying the disease-associated mutation, the proportion of torsinA at the envelope increases. Furthermore, a torsinA mutant that cannot hydrolyze ATP, and therefore becomes trapped on its target protein, selectively localizes to the nuclear periphery.$ `, a. U6 T3 w3 K# ]; [* @: _
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To find out what torsinA binds at the nuclear envelope, the team screened a series of nuclear envelope proteins in cells expressing GFP-labeled torsinA. Overexpression of LAP1, a lamin-associated protein, increased the proportion of perinuclear torsinA, and further analysis demonstrates an association between torsinA and the lumenal domain of LAP1. Based on sequence comparisons, Goodchild and Dauer identified a second torsinA binding protein, LULL1, an ER protein that has a single transmembrane domain and a long lumenal domain similar to that of LAP1. The torsinA-LULL1 association is also dependent on the lumenal region of LULL1.
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( ?3 O) e8 k4 j7 R+ IThe association between lamins, LAP1, and torsinA suggests that torsinA dysfunction may cause problems typical of laminopathies, including improper chromatin organization, transcriptional problems, or overall changes in nuclear architecture. Because the function of AAA ATPase proteins is known—they typically use the energy of ATP hydrolysis to disassemble multiprotein complexes or unfold individual proteins—the researchers think they can use the complex as a launching point to learn about the function of the nuclear envelope.(LULL1 (red) draws torsinA (green) away f) |
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发表于 2009-3-6 09:02
发表于 2015-6-14 00:01
