A Pocket on the Surface of the N-Terminal BRCT Domain of Mcph1 Is Required to Prevent Abnormal Chromosome Condensation

作者：Richards Mark W; Leung Justin W C; Roe S Mark; Li Kaiyi; Chen Junjie; Bayliss Richard^*

来源：Journal of Molecular Biology, 2010, 395(5): 908-915.

DOI：10.1016/j.jmb.2009.11.029

• microcephaly
• Mcph1
• BRCT domain
• premature chromosome condensation
• X-ray crystallography

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 16 angstrom resolution Compared with other BRCT domain structures, the most striking differences are an elongated, ordered beta 1-alpha 1 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.

• 出版日期2010-2-5