The nuclear envelope localization of DYT1 dystonia torsinA-ΔE requires the SUN1 LINC complex component.
The nuclear envelope localization of DYT1 dystonia torsinA-ΔE requires the SUN1 LINC complex component.
复制标题
dyt1 dystonia torsina-ΔE的核包膜定位需要Sun1 linc复合物成分。
DOI：
10.1186/1471-2121-12-24
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发表时间：
2011-05-31
期刊：
影响因子：
--
通讯作者：
Goodchild RE
中科院分区：
文献类型：
--
作者：
Jungwirth MT;Kumar D;Jeong DY;Goodchild RE
DYT1 肌张力障碍是一种常染色体显性神经系统疾病，由从 torsinA (torA) AAA+ 蛋白中去除单个谷氨酸残基 (ΔE) 的突变引起。 TorA 似乎具有核膜 (NE) 局部活性，需要核膜相关多肽 1 (LAP1)，这是一种内核膜局部 torA 结合伴侣。尽管活性低下，但 DYT1 肌张力障碍 torA-ΔE 亚型通常集中在 NE，这表明 torA-ΔE 也与 NE 定位的结合伴侣相互作用。我们确认NE定位的torA-ΔE不与LAP1共免疫沉淀，并发现torA-ΔE继续集中在缺乏LAP1的细胞的NE中。相反，我们发现 torA-ΔE 定位的变异性与组装成 LINC 复合物的 SUN 结构域和 Nesprin 蛋白的存在相关。我们还发现，SUN1 的 siRNA 耗尽（但不是其他 LINC 复合体成分）从 NE 中去除了 torA-ΔE。相比之下，ATP 锁定的 torA 突变体的 LAP1 依赖性 NE 积累不受 LINC 复合蛋白丢失的影响。这种 SUN1 依赖性 torA-ΔE 定位需要 torA 膜关联结构域以及假定的底物相互作用残基 Y147，而这两者都不是 torA 与 LAP1 相互作用所必需的。我们还发现这些基序的突变或 SUN1 的缺失会减少与 NE 标记共定位的 torA-WT 的数量，表明每个基序也是正常 NE 定位的 torA 结合相互作用的基础。这些数据表明，引起 ΔE 突变的疾病促进了 torA 和 SUN1 之间的关联，这与 LAP1 和 ATP 结合的 torA 之间的相互作用不同。两个 NE 定位结合伴侣的证据表明，torA 可能作用于多种底物和/或拥有调节辅因子伴侣。此外，发现 DYT1 突变导致与 SUN1 异常关联，表明 DYT1 肌张力障碍发病机制中存在 LINC 复合体功能障碍，并表明功能获得活动有助于这种显性遗传性疾病。
DYT1 dystonia is an autosomal dominant neurological condition caused by a mutation that removes a single glutamic acid residue (ΔE) from the torsinA (torA) AAA+ protein. TorA appears to possess a nuclear envelope (NE) localized activity that requires Lamina-Associated-Polypeptide 1 (LAP1), which is an inner nuclear membrane localized torA-binding partner. Although hypoactive, the DYT1 dystonia torA-ΔE isoform often concentrates in the NE, suggesting that torA-ΔE also interacts with an NE-localized binding partner. We confirm that NE-localized torA-ΔE does not co-immunoprecipitate with LAP1, and find that torA-ΔE continues to concentrate in the NE of cells that lack LAP1. Instead, we find that variability in torA-ΔE localization correlates with the presence of the SUN-domain and Nesprin proteins that assemble into the LINC complex. We also find that siRNA depletion of SUN1, but not other LINC complex components, removes torA-ΔE from the NE. In contrast, the LAP1-dependent NE-accumulation of an ATP-locked torA mutant is unaffected by loss of LINC complex proteins. This SUN1 dependent torA-ΔE localization requires the torA membrane association domain, as well as a putative substrate-interaction residue, Y147, neither of which are required for torA interaction with LAP1. We also find that mutation of these motifs, or depletion of SUN1, decreases the amount of torA-WT that colocalizes with NE markers, indicating that each also underlies a normal NE-localized torA binding interaction. These data suggest that the disease causing ΔE mutation promotes an association between torA and SUN1 that is distinct to the interaction between LAP1 and ATP-bound torA. This evidence for two NE-localized binding partners suggests that torA may act on multiple substrates and/or possesses regulatory co-factor partners. In addition, finding that the DYT1 mutation causes abnormal association with SUN1 implicates LINC complex dysfunction in DYT1 dystonia pathogenesis, and suggests a gain-of-function activity contributes to this dominantly inherited disease.
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影响因子：
16.8
作者：
Martin, Andreas;Baker, Tania A.;Sauer, Robert T.
通讯作者：
Sauer, Robert T.
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
Goodchild, RE;Dauer, WT
通讯作者：
Dauer, WT
影响因子：
3.5
作者：
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通讯作者：
Breakefield, XO
DOI：
10.1016/j.bbamcr.2008.09.001
发表时间：
2008-12-01
影响因子：
5.1
作者：
Lu, Wenshu;Gotzmann, Josef;Karakesisoglou, Iakowos
通讯作者：
Karakesisoglou, Iakowos
影响因子：
4.8
作者：
MARTIN, L;CRIMAUDO, C;GERACE, L
通讯作者：
GERACE, L