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Characterization of the interactions between Codanin-1 and C15Orf41, two proteins implicated in congenital dyserythropoietic anemia type I disease.
BMC Molecular and Cell Biology ( IF 2.4 ) Pub Date : 2020-03-23 , DOI: 10.1186/s12860-020-00258-1
Grace Swickley 1 , Yehoshua Bloch 1 , Lidor Malka 1 , Adi Meiri 1 , Sharon Noy-Lotan 2 , Amiel Yanai 1 , Hannah Tamary 2, 3 , Benny Motro 1
Affiliation  

BACKGROUND Congenital dyserythropoietic anemia type I (CDA I), is an autosomal recessive disease with macrocytic anemia in which erythroid precursors in the bone marrow exhibit pathognomonic abnormalities including spongy heterochromatin and chromatin bridges. We have shown previously that the gene mutated in CDA I encodes Codanin-1, a ubiquitously expressed and evolutionarily conserved large protein. Recently, an additional etiologic factor for CDA I was reported, C15Orf41, a predicted nuclease. Mutations in both CDAN1 and C15Orf41 genes results in very similar erythroid phenotype. However, the possible relationships between these two etiologic factors is not clear. RESULTS We demonstrate here that Codanin-1 and C15Orf41 bind to each other, and that Codanin-1 stabilizes C15Orf41. C15Orf41 protein is mainly nuclear and Codanin-1 overexpression shifts it to the cytoplasm. Phylogenetic analyses demonstrated that even though Codanin-1 is an essential protein in mammals, it was lost from several diverse and unrelated animal taxa. Interestingly, C15Orf41 was eliminated in the exact same animal taxa. This is an extreme case of the Phylogenetic Profiling phenomenon, which strongly suggests common pathways for these two proteins. Lastly, as the 3D structure is more conserved through evolution than the protein sequence, we have used the Phyre2 alignment program to find structurally homologous proteins. We found that Codanin-1 is highly similar to CNOT1, a conserved protein which serves as a scaffold for proteins involved in mRNA stability and transcriptional control. CONCLUSIONS The physical interaction and the stabilization of C15Orf41 by Codanin-1, combined with the phylogenetic co-existence and co-loss of these two proteins during evolution, suggest that the major function of the presumptive scaffold protein, Codanin-1, is to regulate C15Orf41 activities. The similarity between Codanin-1 and CNOT1 suggest that Codanin-1 is involved in RNA metabolism and activity, and opens up a new avenue for the study of the molecular pathways affected in CDAI.

中文翻译:

表征Codanin-1和C15Orf41之间的相互作用,这两种蛋白与先天性促红细胞生成性贫血I型疾病有关。

背景技术先天性I型人类坏死性贫血(CDA I)是一种常染色体隐性遗传疾病,伴有巨细胞性贫血,其中骨髓中的类胡萝卜素前体表现出病理神经异常,包括海绵状异染色质和染色质桥。先前我们已经证明CDA I中突变的基因编码Codanin-1,这是一种普遍表达且在进化上保守的大蛋白。最近,报道了CDA I的另一个病因,即预测的核酸酶C15Orf41。CDAN1和C15Orf41基因中的突变导致非常相似的类红细胞表型。但是,这两个病因之间的可能关系尚不清楚。结果我们在这里证明了Codanin-1和C15Orf41彼此结合,并且Codanin-1稳定了C15Orf41。C15Orf41蛋白主要是核蛋白,Codanin-1的过表达将其转移到细胞质。系统发育分析表明,即使Codanin-1在哺乳动物中是必不可少的蛋白质,它也从几种不同且无关的动物类群中丢失。有趣的是,C15Orf41在完全相同的动物分类中被淘汰。这是系统发育谱现象的极端情况,它强烈暗示了这两种蛋白的共同途径。最后,由于3D结构在进化过程中比蛋白质序列更保守,因此我们使用了Phyre2比对程序来寻找结构上同源的蛋白质。我们发现Codanin-1与CNOT1非常相似,CNOT1是一种保守的蛋白,可作为参与mRNA稳定性和转录控制的蛋白的支架。结论Codanin-1的物理相互作用和C15Orf41的稳定作用,以及这两种蛋白在进化过程中的系统发育共存和共损失,提示推测的支架蛋白Codanin-1的主要功能是调节C15Orf41活动。Codanin-1和CNOT1之间的相似性表明Codanin-1参与RNA代谢和活性,并为研究CDAI中受影响的分子途径开辟了一条新途径。
更新日期:2020-04-22
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