Saiga Toru, Fukuda Takaichi, Matsumoto Masaki, Tada Hirobumi, Okano Hirotaka James, Okano Hideyuki, Nakayama Keiichi I
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
Mol Cell Biol. 2009 Jul;29(13):3529-43. doi: 10.1128/MCB.00364-09. Epub 2009 Apr 27.
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.
Fbxo45是一种仅存在于神经系统中的F-box蛋白。与其他F-box蛋白不同，由于Cul1结合共有序列中的氨基酸替换，Fbxo45无法形成SCF复合物。蛋白质组学分析表明，Fbxo45特异性地与PAM（与Myc相关的蛋白）结合，PAM是一种环状结构域型泛素连接酶。研究人员构建了Fbxo45基因缺陷小鼠，发现其出生后不久因呼吸窘迫而死亡。Fbxo45(-/-)胚胎表现出膈肌神经支配异常、神经肌肉接头处突触形成受损以及脑内轴突纤维束发育异常。在缺乏Phr1（PAM的小鼠同源物）的小鼠中也观察到类似缺陷，这表明Fbxo45和Phr1在同一通路中发挥作用。此外，Fbxo45(-/-)小鼠的神经元迁移也受到损害。这些结果表明，Fbxo45形成了一种新型的Fbxo45-PAM泛素连接酶复合物，在神经发育中起重要作用。
