Ganesh Subramaniam, Tsurutani Naomi, Suzuki Toshimitsu, Ueda Kazunori, Agarwala Kishan Lal, Osada Hiroyuki, Delgado-Escueta Antonio V, Yamakawa Kazuhiro
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wakoshi 351-0198, Japan.
Hum Mol Genet. 2003 Sep 15;12(18):2359-68. doi: 10.1093/hmg/ddg253. Epub 2003 Jul 29.
Lafora disease is an autosomal recessive type of progressive myoclonus epilepsy caused by mutations in the EPM2A gene. The EPM2A gene-encoded protein laforin is a dual-specificity phosphatase that associates with polyribosomes. Because the cellular functions of laforin are largely unknown, we used the yeast-two hybrid system to screen for protein(s) that interact with laforin. We found that laforin interacts with a phylogenetically conserved protein HIRIP5 that harbors a NifU-like domain. Both in vitro and in vivo assay have shown that the interaction is specific and that laforin probably uses its N-terminal CBD-4 domain to interact with the C-terminal NifU-like domain of the HIRIP5 protein. HIRIP5 encodes a cytosolic protein and is expressed ubiquitously, perhaps reflecting a house-keeping function. The presence of a NifU-like domain in the HIRIP5 protein raises an interesting possibility that it may be involved in iron homeostasis. Although the significance of the interaction between HIRIP5 and laforin proteins is not yet fully known, because laforin dephosphorylated HIRIP5 in vitro, HIRIP5 promises to be an interesting laforin-binding partner and would contribute to the understanding of the molecular pathology of Lafora disease.
拉福拉病是一种常染色体隐性进行性肌阵挛性癫痫，由EPM2A基因突变引起。EPM2A基因编码的蛋白拉福林是一种与多核糖体相关的双特异性磷酸酶。由于拉福林的细胞功能在很大程度上尚不清楚，我们利用酵母双杂交系统筛选与拉福林相互作用的蛋白质。我们发现拉福林与一种具有NifU样结构域的系统发育保守蛋白HIRIP5相互作用。体外和体内试验均表明这种相互作用是特异性的，拉福林可能利用其N端CBD-4结构域与HIRIP5蛋白的C端NifU样结构域相互作用。HIRIP5编码一种胞质蛋白，且在全身广泛表达，这可能反映了一种管家功能。HIRIP5蛋白中存在NifU样结构域引发了一种有趣的可能性，即它可能参与铁稳态。虽然HIRIP5与拉福林蛋白之间相互作用的意义尚未完全明确，但由于拉福林在体外使HIRIP5去磷酸化，HIRIP5有望成为一个有趣的拉福林结合伴侣，并有助于理解拉福拉病的分子病理学。
