2. Academic Validation
  3. Intrinsic disorder drives N-terminal ubiquitination by Ube2w

Intrinsic disorder drives N-terminal ubiquitination by Ube2w

  • Nat Chem Biol. 2015 Jan;11(1):83-9. doi: 10.1038/nchembio.1700.
Vinayak Vittal 1,  Lei Shi 2,  Dawn M Wenzel 1,  K Matthew Scaglione 3,  Emily D Duncan 1,  Venkatesha Basrur 4,  Kojo S J Elenitoba-Johnson 4,  David Baker 2,  Henry L Paulson 5,  Peter S Brzovic 1,  Rachel E Klevit 1
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Washington, Seattle, Washington, USA.
  • 2 1] Department of Biochemistry, University of Washington, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
  • 3 1] Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA. [2] Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA. [3] Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • 4 Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • 5 Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
PMID: 25436519 DOI: 10.1038/nchembio.1700
Abstract

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 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.

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