Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development
Fbxo45 Forms a Novel Ubiquitin Ligase Complex and Is Required for Neuronal Development
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DOI：
10.1128/mcb.00364-09
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
--
作者：
Saiga, Toru;Fukuda, Takaichi;Nakayama, Keiichi I.
Fbxo45是一种仅限于神经系统的F-box蛋白。与其他F-box蛋白不同的是，Fbxo45不是由于Cul1结合的共同序列中的氨基酸替换而形成SCF复合体。蛋白质组学分析表明，Fbxo45与环指型泛素连接酶PAM(与Myc相关的蛋白)特异性结合。Fbxo45基因缺陷的小鼠被培育出来，发现出生后不久就死于呼吸窘迫。Fbxo45(-/-)胚胎表现为横隔膜的异常神经支配，神经肌肉接头处突触形成受损，以及大脑中轴突纤维束的异常发育。在缺乏Phr1(PAM的小鼠同源基因)的小鼠中也观察到类似的缺陷，这表明Fbxo45和Phr1的功能相同。此外，Fbxo45(-/-)小鼠的神经元迁移受到损害。这些结果表明，Fbxo45形成了一种新的Fbxo45-PAM泛素连接酶复合体，在神经发育中发挥着重要作用。
Fbxo45 is an F-box protein that is restricted to the nervous system. Unlike other F-box proteins, Fbxo45 was found not to form an SCF complex as a result of an amino acid substitution in the consensus sequence for Cul1 binding. Proteomics analysis revealed that Fbxo45 specifically associates with PAM (protein associated with Myc), a RING finger-type ubiquitin ligase. Mice deficient in Fbxo45 were generated and found to die soon after birth as a result of respiratory distress. Fbxo45(-/-) embryos show abnormal innervation of the diaphragm, impaired synapse formation at neuromuscular junctions, and aberrant development of axon fiber tracts in the brain. Similar defects are also observed in mice lacking Phr1 (mouse ortholog of PAM), suggesting that Fbxo45 and Phr1 function in the same pathway. In addition, neuronal migration was impaired in Fbxo45(-/-) mice. These results suggest that Fbxo45 forms a novel Fbxo45-PAM ubiquitin ligase complex that plays an important role in neural development.