Journal
NATURE CHEMICAL BIOLOGY
Volume 11, Issue 1, Pages 83-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1700
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Funding
- National Institute of General Medical Sciences [R01 GM088055, R01 GM098503, K99 NS073936, R01 AG034228]
- University of Washington Hurd Fellowship Fund
- Public Health Service National Research Service Award [2T32 GM007270]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM088055, T32GM007270, R01GM098503] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R00NS073936, K99NS073936] Funding Source: NIH RePORTER
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Ubiquitination of the alpha 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 alpha-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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