title: Specific recognition of phosphorylated tail of H2AX by the tandem BRCT domains of MCPH1 revealed by complex structure.
abstract: MCPH1 is especially important for linking chromatin remodeling to DNA damage response. It contains three BRCT (BRCA1-carboxyl terminal) domains. The N-terminal region directly binds with chromatin remodeling complex SWI-SNF, and the C-terminal BRCT2-BRCT3 domains (tandem BRCT domains) are involved in cellular DNA damage response. The MCPH1 gene associates with evolution of brain size, and its variation can cause primary microcephaly. In this study we solve the crystal structures of MCPH1 natural variant (A761) C-terminal tandem BRCT domains alone as well as in complex with γH2AX tail. Compared with other structures of tandem BRCT domains, the most significant differences lie in phosphopeptide binding pocket. Additionally, fluorescence polarization assays demonstrate that MCPH1 tandem BRCT domains show a binding selectivity on pSer +3 and prefer to bind phosphopeptide with free COOH-terminus. Taken together, our research provides new structural insights into BRCT-phosphopeptide recognition mechanism.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, PR China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Shao
authors.forename: Fudong
authors.initials: F
authors.lastname: Li
authors.forename: Shirley M-H
authors.initials: SM
authors.lastname: Sy
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Deshun
authors.initials: D
authors.lastname: Gong
authors.forename: Bin
authors.initials: B
authors.lastname: Wen
authors.forename: Michael S Y
authors.initials: MS
authors.lastname: Huen
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Gong
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D003598:Cytoskeletal Proteins; D006657:Histones / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D010750:Phosphoproteins / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D013499:Surface Properties
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C468783:H2AX protein, human; D006657:Histones; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins