Structural Insights into E1-Catalyzed Ubiquitin Activation and Transfer to Conjugating Enzymes
Ubiquitin (Ub) and ubiquitin-like proteins (Ubls) are conjugated to their targets by specific cascades involving three classes of enzymes, E1, E2, and E3. Each E1 adenylates the C terminus of its cognate Ubl, forms a E1{approx}Ubl thioester intermediate, and ultimately generates a thioester-linked E2{approx}Ubl product. We have determined the crystal structure of yeast Uba1, revealing a modular architecture with individual domains primarily mediating these specific activities. The negatively charged C-terminal ubiquitin-fold domain (UFD) is primed for binding of E2s and recognizes their positively charged first a helix via electrostatic interactions. In addition, a mobile loop from the domain harboring the E1 catalytic cysteine contributes to E2 binding. Significant, experimentally observed motions in the UFD around a hinge in the linker connecting this domain to the rest of the enzyme suggest a conformation-dependent mechanism for the transthioesterification function of Uba1; however, this mechanism clearly differs from that of other E1 enzymes.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 959561
- Report Number(s):
- BNL-82547-2009-JA; CELLB5; TRN: US201016%%705
- Journal Information:
- Cell, Vol. 134, Issue 2; ISSN 0092-8674
- Country of Publication:
- United States
- Language:
- English
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