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

DOI: 10.1016/j.jmb.2009.11.029 DOI Help
PMID: 19925808 PMID Help

Authors: Mark Richards (Institute of Cancer Research) , Justin Leung (The University of Texas M.D. Anderson Cancer Center) , Junji Chen (The University of Texas M.D. Anderson Cancer Center) , Richard Bayliss (Institute of Cancer Research) , Mark Roe (Institute of Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: November 2009
Diamond Proposal Number(s): 6385

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 Å resolution. Compared with other BRCT domain structures, the most striking differences are an elongated, ordered ?1–?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.

Journal Keywords: Amino; Animals; Binding; Chromosome; Chromosomes; Human; Crystallography; X-Ray; Genes; Recessive; Humans; Mice; Mice; Knockout; Microcephaly; Models; Molecular; Mutation; Missense; Nerve; Protein; Tertiary; Sequence; Amino; Syndrome

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography

Added On: 07/12/2009 14:17

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