Abstract
BackgroundThe 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.ResultsUsing 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.ConclusionsStructural 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.ReviewersThis article was reviewed by Eugene Koonin, Balaji Santhanam, Kira S. Makarova.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-015-0066-5) contains supplementary material, which is available to authorized users.
Highlights
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 motif is variable among different Really Interesting New Gene (RING)-like treble clefs, for example, in the B-box and ZZ domain, the commonly observed metal-chelating motif is CC/HCCCCHH and CCCCCCHH, respectively
The zinc ion of the treble clef is numbered ‘1’, the second zinc ion seen in binuclear treble clefs is numbered ‘2’ and the third zinc ion of the ubiquitin ligase N-recognin (UBR)-box is numbered ‘3’. β-strands are represented as arrows and α-helices are shown as rectangles/cylinders
Summary
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. The N-end rule pathway relates the biological half-life of cellular proteins to the presence of N-terminal destabilizing signals (N-degrons), which upon being recognized by N-recognins, targets the substrate protein for proteolysis [1]. Two branches of the N-end rule pathway, viz., the Arg/N-end rule and the Ac/N-end rule recognize and target different sets of N-degrons [1]. N-recognins of the eukaryotic Arg/N-end rule are distinguished by the presence of a type 1 N-degron recognizing UBR-box domain [1, 2]. The X-ray structures of UBR-box from human UBR1 and UBR2 (PDB identifiers 3NY1_A and 3NY3_A, respectively) [4] and S. cerevisiae UBR1 (PDB identifier 3NIJ_A) [5] are available (Fig. 1a,b), both
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