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Title: A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.
Authors: Richards, MW
Leung, JW
Roe, SM
Li, K
Chen, J
Bayliss, R
First Published: 5-Feb-2010
Citation: J MOL BIOL, 2010, 395 (5), pp. 908-915
Abstract: 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.
DOI Link: 10.1016/j.jmb.2009.11.029
eISSN: 1089-8638
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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