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首页> 外文期刊>Journal of Molecular Biology >A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.
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A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.

机译：Mcph1的N端BRCT结构域表面需要一个口袋，以防止异常染色体凝缩。

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摘要

Mcph1 is mutated in autosomal recessive primary microcephaly and premature chromosome condensation (PCC) syndrome. Increased chromosome condensation is a common feature of cells isolated from patients afflicted with either disease. Normal cells depleted of Mcph1 also exhibit PCC phenotype. Human Mcph1 contains three BRCA1-carboxyl terminal (BRCT) domains, the first of which (Mcph1N) is necessary for the prevention of PCC. The only known disease-associated missense mutation in Mcph1 resides in this domain (T27R). We have determined the X-ray crystal structure of human Mcph1N to 1.6 A resolution. Compared with other BRCT domain structures, the most striking differences are an elongated, ordered beta1-alpha1 loop and an adjacent hydrophobic pocket. This pocket is in the equivalent structural position to the phosphate binding site of BRCT domains that recognize phospho-proteins, although the phosphate-binding residues are absent in Mcph1N. Mutations in the pocket abrogate the ability of full-length Mcph1 to rescue the PCC phenotype of Mcph1(-/-) mouse embryonic fibroblast cells, suggesting that it forms an essential part of a protein-protein interaction site necessary to prevent PCC.
机译：Mcph1在常染色体隐性原发性小头畸形和早熟染色体浓缩（PCC）综合征中发生突变。染色体凝结增加是从患有任何一种疾病的患者中分离出的细胞的共同特征。耗尽Mcph1的正常细胞也表现出PCC表型。人Mcph1包含三个BRCA1-羧基末端（BRCT）域，其中第一个（Mcph1N）域对于预防PCC是必需的。 Mcph1中唯一已知的与疾病相关的错义突变位于该域（T27R）中。我们确定了人类Mcph1N的X射线晶体结构为1.6 A分辨率。与其他BRCT域结构相比，最显着的差异是细长的有序beta1-alpha1环和相邻的疏水袋。尽管Mcph1N中不存在磷酸结合残基，但该口袋的位置与识别磷酸蛋白的BRCT域的磷酸结合位点的结构相同。口袋中的突变消除了全长Mcph1抢救Mcph1（-/-）小鼠胚胎成纤维细胞PCC表型的能力，这表明它形成了预防PCC所需的蛋白质-蛋白质相互作用位点的重要组成部分。

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