Dataset Information

Intrinsic disorder drives N-terminal ubiquitination by Ube2w.

ABSTRACT: Ubiquitination of the ?N-terminus of protein substrates has been reported sporadically since the early 1980s. However, the identity of an enzyme responsible for this unique ubiquitin (Ub) modification has only recently been elucidated. We show the Ub-conjugating enzyme (E2) Ube2w uses a unique mechanism to facilitate the specific ubiquitination of the ?-amino group of its substrates that involves recognition of backbone atoms of intrinsically disordered N termini. We present the NMR-based solution ensemble of full-length Ube2w that reveals a structural architecture unlike that of any other E2 in which its C terminus is partly disordered and flexible to accommodate variable substrate N termini. Flexibility of the substrate is critical for recognition by Ube2w, and either point mutations in or the removal of the flexible C terminus of Ube2w inhibits substrate binding and modification. Mechanistic insights reported here provide guiding principles for future efforts to define the N-terminal ubiquitome in cells.

SUBMITTER: Vittal V

PROVIDER: S-EPMC4270946 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Intrinsic disorder drives N-terminal ubiquitination by Ube2w.

Vittal Vinayak V Shi Lei L Wenzel Dawn M DM Scaglione K Matthew KM Duncan Emily D ED Basrur Venkatesha V Elenitoba-Johnson Kojo S J KS Baker David D Paulson Henry L HL Brzovic Peter S PS Klevit Rachel E RE

Nature chemical biology 20141201 1

Ubiquitination of the αN-terminus of protein substrates has been reported sporadically since the early 1980s. However, the identity of an enzyme responsible for this unique ubiquitin (Ub) modification has only recently been elucidated. We show the Ub-conjugating enzyme (E2) Ube2w uses a unique mechanism to facilitate the specific ubiquitination of the α-amino group of its substrates that involves recognition of backbone atoms of intrinsically disordered N termini. We present the NMR-based soluti ...[more]

PMID: 25436519

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Project description:Intrinsically disordered regions (IDRs) of proteins play significant biological functional roles despite lacking a well-defined 3D structure. For example, IDRs provide efficient housing for large numbers of post-translational modification (PTM) sites in eukaryotic proteins. Here, we study the distribution of more than 15,000 experimentally determined human methylation, acetylation and ubiquitination sites (collectively termed 'MAU' sites) in ordered and disordered regions, and analyse their conservation across 380 eukaryotic species. Conservation signals for the maintenance and novel emergence of MAU sites are examined at 11 evolutionary levels from the whole eukaryotic domain down to the ape superfamily, in both ordered and disordered regions. We discover that MAU PTM is a major driver of conservation for arginines and lysines in both ordered and disordered regions, across the 11 levels, most significantly across the mammalian clade. Conservation of human methylatable arginines is very strongly favoured for ordered regions rather than for disordered, whereas methylatable lysines are conserved in either set of regions, and conservation of acetylatable and ubiquitinatable lysines is favoured in disordered over ordered. Notably, we find evidence for the emergence of new lysine MAU sites in disordered regions of proteins in deuterostomes and mammals, and in ordered regions after the dawn of eutherians. For histones specifically, MAU sites demonstrate an idiosyncratic significant conservation pattern that is evident since the last common ancestor of mammals. Similarly, folding-on-binding (FB) regions are highly enriched for MAU sites relative to either ordered or disordered regions, with ubiquitination sites in FBs being highly conserved at all evolutionary levels back as far as mammals. This investigation clearly demonstrates the complex patterns of PTM evolution across the human proteome and that it is necessary to consider conservation of sequence features at multiple evolutionary levels in order not to get an incomplete or misleading picture.

Dataset Information

Intrinsic disorder drives N-terminal ubiquitination by Ube2w.

Publications

Intrinsic disorder drives N-terminal ubiquitination by Ube2w.

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