title: The bridge-region of the Ku superfamily is an atypical zinc ribbon domain.
abstract: Members of the Ku superfamily are DNA-end-binding proteins involved in non-homologous end-joining (NHEJ) DNA repair. The published crystal structure of human Ku-DNA complex reveals a heterodimer that forms a ring around dsDNA by means of the Ku core modules. These modules contain a highly conserved seven-stranded β-barrel, which in turn contains an insertion, termed the bridge-region, between its second and third β-strands. The bridge-region adopts an unusual β-strand-rich structure critical for dsDNA-binding and Ku function, but its provenance remains unclear. Here, we demonstrate that the bridge-region of Ku is a novel member of the diverse Zn-ribbon fold group. Sequence analysis reveals that Ku from several Gram-positive bacteria and bacteriophages retain metal-chelating motifs, whereas they have been lost in the versions from most other organisms. Structural comparisons suggest that the Zn-ribbon from Ku-bridge-region is the first example of a circularly permuted, segment-swapped Zn-ribbon. This finding helps explain how Ku is likely to bind DNA as an obligate dimer. Further, we hypothesize that retention of the unusual conformation of the turns of the Zn-ribbons, despite loss of the Zn-binding sites, provides clues regarding the mechanism by which the Ku-bridge-regions sense the DNA state.
authors.affiliation: Center for Research in Biological Systems, University of California, San Diego, La Jolla, CA 92093, USA. krishna@sdsc.edu
authors.forename: S Sri
authors.initials: SS
authors.lastname: Krishna
authors.forename: L
authors.initials: L
authors.lastname: Aravind
mesh_terms: D000595:Amino Acid Sequence; D004265:DNA Helicases / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D000072200:Ku Autoantigen; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D004268:DNA-Binding Proteins; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen