title: Structure of a human ASF1a-HIRA complex and insights into specificity of histone chaperone complex assembly.
abstract: Human HIRA, ASF1a, ASF1b and CAF-1 are evolutionally conserved histone chaperones that form multiple functionally distinct chromatin-assembly complexes, with roles linked to diverse nuclear process, such as DNA replication and formation of heterochromatin in senescent cells. We report the crystal structure of an ASF1a-HIRA heterodimer and a biochemical dissection of ASF1a's mutually exclusive interactions with HIRA and the p60 subunit of CAF-1. The HIRA B domain forms an antiparallel beta-hairpin that binds perpendicular to the strands of the beta-sandwich of ASF1a, via beta-sheet, salt bridge and van der Waals contacts. The N- and C-terminal regions of ASF1a and ASF1b determine the different affinities of these two proteins for HIRA, by contacting regions outside the HIRA B domain. CAF-1 p60 also uses B domain-like motifs for binding to ASF1a, thereby competing with HIRA. Together, these studies begin to define the molecular determinants of assembly of functionally diverse macromolecular histone chaperone complexes.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Poustovoitov
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhao
authors.forename: Megan
authors.initials: M
authors.lastname: Garfinkel
authors.forename: Adrian
authors.initials: A
authors.lastname: Canutescu
authors.forename: Roland
authors.initials: R
authors.lastname: Dunbrack
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D056488:Histone Chaperones; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry*; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection
chemical_list: C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; D014157:Transcription Factors