E2-RING Expansion of the NEDD8 Cascade Confers Specificity to Cullin Modification

Huang, D. T. , Ayrault, O., Hunt, H. W., Taherbhoy, A. M., Duda, D. M., Scott, D. C., Borg, L. A., Neale, G., Murray, P. J. and Roussel, M. F. (2009) E2-RING Expansion of the NEDD8 Cascade Confers Specificity to Cullin Modification. Molecular Cell, 33(4), pp. 483-495. (doi: 10.1016/j.molcel.2009.01.011)

Abstract

Ubiquitin and ubiquitin-like proteins (UBLs) are directed to targets by cascades of El, E2, and E3 enzymes. The largest ubiquitin E3 subclass consists of cullin-RING ligases (CRLs), which contain one each of several cullins (CUL1, -2, -3, -4, or -5) and RING proteins (RBX1 or -2). CRLs are activated by ligation of the UBL NEDD8 to a conserved cullin lysine. How is cullin NEDD8ylation specificity established? Here we report that, like UBE2M (also known as UBC12), the previously uncharacterized E2 UBE2F is a NEDD8-conjugating enzyme in vitro and in vivo. Biochemical and structural analyses indicate how plasticity of hydrophobic E1-E2 interactions and El conformational flexibility allow one El to charge multiple E2s. The E2s; have distinct functions, with UBE2M/RBX1 and UBE2F/RBX2 displaying different target cullin specificities. Together, these studies reveal the molecular basis for and functional importance of hierarchical expansion of the NEDD8 conjugation system in establishing selective CRL activation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Huang, Professor Danny
• Authors: Huang, D. T., Ayrault, O., Hunt, H. W., Taherbhoy, A. M., Duda, D. M., Scott, D. C., Borg, L. A., Neale, G., Murray, P. J., and Roussel, M. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cell
• ISSN: 1097-2765
• Published Online: 01 January 2009