Becker Emmanuelle, Meyer Vincent, Madaoui Hocine, Guerois Raphaël
Service de Biophysique des Fonctions Membranaires, URA CNRS 2096, Département de Biologie Joliot-Curie, CEA Saclay, 91191 Gif-Sur-Yvette Cedex, France.
Bioinformatics. 2006 Jun 1;22(11):1289-92. doi: 10.1093/bioinformatics/btl075. Epub 2006 Mar 7.
Human Nbs1 and its homolog Xrs2 in Saccharomyces cerevisiae are part of the conserved MRN complex (MRX in yeast) which plays a crucial role in maintaining genomic stability. NBS1 corresponds to the gene mutated in the Nijmegen breakage syndrome (NBS) known as a radiation hyper-sensitive disease. Despite the conservation and the importance of the MRN complex, the high sequence divergence between Nbs1 and Xrs2 precluded the identification of common domains downstream of the N-terminal Fork-Head Associated (FHA) domain.
Using HMM-HMM profile comparisons and structure modelling, we assessed the existence of a tandem BRCT in both Nbs1 and Xrs2 after the FHA. The structure-based conservation analysis of the tandem BRCT in Nbs1 supports its function as a phosphoserine binding domain. Remarkably, the 5 bp deletion observed in 95% of NBS patients cleaves the tandem at the linker region while preserving the structural integrity of each BRCT domain in the resulting truncated gene products.
人类Nbs1及其在酿酒酵母中的同源物Xrs2是保守的MRN复合物（酵母中的MRX）的一部分，该复合物在维持基因组稳定性方面起着至关重要的作用。NBS1对应于尼曼-匹克氏综合征（NBS）中发生突变的基因，NBS是一种辐射超敏疾病。尽管MRN复合物具有保守性和重要性，但Nbs1和Xrs2之间高度的序列差异使得在N端叉头相关（FHA）结构域下游难以识别共同的结构域。
通过隐马尔可夫模型（HMM）-HMM轮廓比较和结构建模，我们评估了FHA结构域之后Nbs1和Xrs2中串联BRCT结构域的存在情况。基于结构的Nbs1串联BRCT保守性分析支持其作为磷酸丝氨酸结合结构域发挥功能。值得注意的是，在95%的NBS患者中观察到通过5bp缺失在连接区切割串联结构，同时在所得截短的基因产物中保留每个BRCT结构域的结构完整性。
