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 β1-α1 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.
Original language | English (US) |
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Pages (from-to) | 908-915 |
Number of pages | 8 |
Journal | Journal of Molecular Biology |
Volume | 395 |
Issue number | 5 |
DOIs | |
State | Published - Feb 5 2010 |
Externally published | Yes |
Keywords
- BRCT domain
- Mcph1
- X-ray crystallography
- microcephaly
- premature chromosome condensation
ASJC Scopus subject areas
- Molecular Biology
- Biophysics
- Structural Biology