Molecular determinants of survival motor neuron (SMN) protein cleavage by the calcium-activated protease, calpain.
Molecular determinants of survival motor neuron (SMN) protein cleavage by the calcium-activated protease, calpain.
复制标题
DOI：
10.1371/journal.pone.0015769
复制
发表时间：
2010-12-30
期刊：
影响因子：
3.7
通讯作者：
Matera AG
中科院分区：
文献类型：
--
作者：
Fuentes JL;Strayer MS;Matera AG
脊髓性肌萎缩症（SMA）是儿童死亡的主要遗传原因，由运动神经元存活蛋白（SMN）水平降低引起。SMN在小核核糖核蛋白（snRNP）的生物发生中作为大复合体的一部分发挥作用。目前尚不清楚是否snRNP生物合成缺陷导致SMA或一些组织特异性功能的丧失导致疾病。我们最近证明了SMN复合物定位于骨骼肌和心肌肌节的Z盘，并且SMN是钙蛋白酶的蛋白水解靶点。钙蛋白酶与肌肉和神经退行性疾病有关，尽管它们与SMA的关系尚不清楚。使用质谱，我们确定了两个相邻的钙蛋白酶切割位点的SMN，S192和F193。这些位点周围区域的小基序的缺失抑制了切割。SMN内患者来源的SMA突变减少了钙蛋白酶裂解。据报道，SMN（D44 V）可损害Gemin 2结合和氨基末端SMN结合，显著抑制切割，表明这些相互作用在调节钙蛋白酶切割中的作用。缺失A188，一个在SMA I型（A188 S）中突变的残基，废除了钙蛋白酶切割，突出了该区域的重要性。相反，干扰SMN、Y272 C和SMNΔ7自身寡聚化的SMA突变对切割没有影响。去除最近鉴定的SMN降解决定子（Δ268-294）导致钙蛋白酶敏感性增加，表明SMN的C末端在决定切割位点的可用性方面很重要。对SMN切割的空间决定因素的研究表明，内源性钙蛋白酶可以切割胞质，但不能切割核SMN。总的来说，这些结果提供了一个新的方面的翻译后调节SMN的洞察。
Spinal muscular atrophy (SMA) is a leading genetic cause of childhood mortality, caused by reduced levels of survival motor neuron (SMN) protein. SMN functions as part of a large complex in the biogenesis of small nuclear ribonucleoproteins (snRNPs). It is not clear if defects in snRNP biogenesis cause SMA or if loss of some tissue-specific function causes disease. We recently demonstrated that the SMN complex localizes to the Z-discs of skeletal and cardiac muscle sarcomeres, and that SMN is a proteolytic target of calpain. Calpains are implicated in muscle and neurodegenerative disorders, although their relationship to SMA is unclear. Using mass spectrometry, we identified two adjacent calpain cleavage sites in SMN, S192 and F193. Deletion of small motifs in the region surrounding these sites inhibited cleavage. Patient-derived SMA mutations within SMN reduced calpain cleavage. SMN(D44V), reported to impair Gemin2 binding and amino-terminal SMN association, drastically inhibited cleavage, suggesting a role for these interactions in regulating calpain cleavage. Deletion of A188, a residue mutated in SMA type I (A188S), abrogated calpain cleavage, highlighting the importance of this region. Conversely, SMA mutations that interfere with self-oligomerization of SMN, Y272C and SMNΔ7, had no effect on cleavage. Removal of the recently-identified SMN degron (Δ268-294) resulted in increased calpain sensitivity, suggesting that the C-terminus of SMN is important in dictating availability of the cleavage site. Investigation into the spatial determinants of SMN cleavage revealed that endogenous calpains can cleave cytosolic, but not nuclear, SMN. Collectively, the results provide insight into a novel aspect of the post-translation regulation of SMN.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2005.05.010
发表时间：
2005-07-08
影响因子：
3.1
作者：
Barnoy, S;Maki, M;Kosower, NS
通讯作者：
Kosower, NS
影响因子：
8
作者：
Bertoli, C.;Copetti, T.;Schneider, C.
通讯作者：
Schneider, C.
影响因子：
5
作者：
Arnold, AS;Gueye, M;Gies, JP
通讯作者：
Gies, JP
影响因子：
3.5
作者：
Coovert, DD;Le, TT;Burghes, AHM
通讯作者：
Burghes, AHM
影响因子：
5.3
作者：
Carrel, Tessa L.;McWhorter, Michelle L.;Beattie, Christine E.
通讯作者：
Beattie, Christine E.