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

JOURNAL OF MOLECULAR BIOLOGY

卷:395

Article

Richards, Mark W.¹  Leung, Justin W. C.²  Roe, S. Mark¹  Li, Kaiyi³  Chen, Junjie²  Bayliss, Richard¹ 

[1] Inst Canc Res, Sect Struct Biol, Chester Beatty Labs, London SW3 6JB, England

[2] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Surg, Houston, TX 77030 USA

关键词: microcephaly;    Mcph1;    BRCT domain;    premature chromosome condensation;    X-ray crystallography;   

DOI  :  10.1016/j.jmb.2009.11.029

来源: Elsevier

【 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 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. (C) 2009 Elsevier Ltd. All rights reserved

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