Dataset Information

The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers.

ABSTRACT: 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.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.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.

SUBMITTER: Kaur G

PROVIDER: S-EPMC4506424 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Publications

The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers.

Kaur Gurmeet G Subramanian Srikrishna S

Biology direct 20150717

<h4>Background</h4>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.<h4>Results</h4>Using sequence and structure analysis we argue that the UBR-box fold emerged from a binuclear RING-like treble clef zinc fi ...[more]

PMID: 26185100

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Project description:Recent studies point to a diverse assemblage of prokaryotic cognates of the eukaryotic ubiquitin (Ub) system. These systems span an entire spectrum, ranging from those catalyzing cofactor and amino acid biosynthesis, with only adenylating E1-like enzymes and ubiquitin-like proteins (Ubls), to those that are closer to eukaryotic systems by virtue of possessing E2 enzymes. Until recently E3 enzymes were unknown in such prokaryotic systems. Using contextual information from comparative genomics, we uncover a diverse group of RING finger E3s in prokaryotes that are likely to function with E1s, E2s, JAB domain peptidases and Ubls. These E1s, E2s and RING fingers suggest that features hitherto believed to be unique to eukaryotic versions of these proteins emerged progressively in such prokaryotic systems. These include the specific configuration of residues associated with oxyanion-hole formation in E2s and the C-terminal UFD in the E1 enzyme, which presents the E2 to its active site. Our study suggests for the first time that YukD-like Ubls might be conjugated by some of these systems in a manner similar to eukaryotic Ubls. We also show that prokaryotic RING fingers possess considerable functional diversity and that not all of them are involved in Ub-related functions. In eukaryotes, other than RING fingers, a number of distinct binuclear (chelating two Zn atoms) and mononuclear (chelating one zinc atom) treble clef domains are involved in Ub-related functions. Through detailed structural analysis we delineated the higher order relationships and interaction modes of binuclear treble clef domains. This indicated that the FYVE domain acquired the binuclear state independently of the other binuclear forms and that different treble clef domains have convergently acquired Ub-related functions independently of the RING finger. Among these, we uncover evidence for notable prokaryotic radiations of the ZF-UBP, B-box, AN1 and LIM clades of treble clef domains and present contextual evidence to support their role in functions unrelated to the Ub-system in prokaryotes. In particular, we show that bacterial ZF-UBP domains are part of a novel cyclic nucleotide-dependent redox signaling system, whereas prokaryotic B-box, AN1 and LIM domains have related functions as partners of diverse membrane-associated peptidases in processing proteins. This information, in conjunction with structural analysis, suggests that these treble clef domains might have been independently recruited to the eukaryotic Ub-system due to an ancient conserved mode of interaction with peptides.

Dataset Information

The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers.

Publications

The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers.

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