NDLI: Basis for a ubiquitin-like protein thioester switch toggling E1-E2 affinity

Content Provider	PubMed Central
Author	Huang, Danny T. Hunt, Harold W. Zhuang, Min Ohi, Melanie D. Holton, James M. Schulman, Brenda A.
Abstract	Ubiquitin-like proteins (Ubls) are conjugated by dynamic E1-E2-E3 enzyme cascades. E1s activate Ubls by catalyzing Ubl C-terminal adenylation, forming a covalent E1~Ubl thioester intermediate, and generating a thioester-linked E2~Ubl product, which must be released for subsequent reactions. We report structural analysis of a trapped Ubl activation complex containing NEDD8’s heterodimeric E1 (APPBP1-UBA3), two NEDD8s (one thioester-linked to E1, one noncovalently-associated for adenylation), a catalytically-inactive E2 (Ubc12), and MgATP. The results suggest that a thioester switch toggles E1-E2 affinities. Two E2 binding sites depend on NEDD8 being thioester-linked to E1. One is unmasked by a striking E1 conformational change. The other comes directly from the thioester-bound NEDD8. After NEDD8 transfer to E2, reversion to an alternate E1 conformation would facilitate release of the E2~NEDD8 thioester product. Thus, transferring the Ubl’s thioester linkage between successive conjugation enzymes can induce conformational changes and alter interaction networks to drive consecutive steps in Ubl cascades.
Related Links	http://dx.doi.org/10.1038/nature05490
Ending Page	398
Page Count	5
Starting Page	394
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7126
Volume Number	445
Language	English
Publisher Date	2007-01-25
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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