title: The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers.
abstract: BACKGROUND
  The N-end rule pathway is a part of the ubiquitin-dependent proteolytic system wherein N-recognin proteins recognize the amino terminal degradation signals (N-degrons) of the substrate. The type 1 N-degron recognizing UBR-box domain of the eukaryotic Arg/N-end rule pathway is known to possess a novel three-zinc-stabilized heart-shaped fold.
  
  
  RESULTS
  Using sequence and structure analysis we argue that the UBR-box fold emerged from a binuclear RING-like treble clef zinc finger. The RING-like core is preserved in the UBR-box and the metal-chelating motifs display significant sequence and structural similarity to B-box and ZZ domains. UBR-box domains retrieved in our analysis co-occur with a variety of other protein domains, suggestive of its involvement in diverse biological roles. The UBR-box is a unique family of RING-like treble clefs as it displays a distinct circular permutation at the zinc-knuckle of the first zinc-binding site unlike other documented permutations of the RING-like domains which occur at the second zinc-binding site. The circular permutation of the RING-like treble clef scaffold has possibly aided the gain of a novel and relatively deep cleft suited for binding N-degrons. The N- and C-terminal extensions to the circularly permuted RING-like region bind a third zinc ion, which likely provides additional stability to the domain by keeping the two halves of the permuted zinc-knuckle together.
  
  
  CONCLUSIONS
  Structural modifications and extensions to the RING-like core have resulted in a novel UBR-box fold, which can recognize and target the type 1 N-degron containing proteins for ubiquitin-mediated proteolysis. The UBR-box appears to have emerged during the expansion of ubiquitin system pathway-related functions in eukaryotes, but is also likely to have other non-N-recognin functions as well.
authors.affiliation: CSIR-Institute of Microbial Technology (IMTECH), Sector 39-A, Chandigarh, 160036, India. gurmeetkaur@imtech.res.in.
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Kaur
authors.affiliation: CSIR-Institute of Microbial Technology (IMTECH), Sector 39-A, Chandigarh, 160036, India. krishna@imtech.res.in.
authors.forename: Srikrishna
authors.initials: S
authors.lastname: Subramanian
mesh_terms: D056890:Eukaryota / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D044767:Ubiquitin-Protein Ligases