A pocket on the surface of the N-terminal BRCT domain of Mcph1 is required to prevent abnormal chromosome condensation.
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.
Richards
Mark W
MW
Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
Leung
Justin W C
JW
Roe
S Mark
SM
Li
Kaiyi
K
Chen
Junjie
J
Bayliss
Richard
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018797:Cell Cycle Proteins; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism; D002877:Chromosomes, Human / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins; D005808:Genes, Recessive; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins