Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl

Dou, H., Buetow, L., Hock, A., Sibbet, G.J., Vousden, K.H. and Huang, D.T. (2012) Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl. Nature Structural and Molecular Biology, 19(2), pp. 184-192. (doi: 10.1038/nsmb.2231)

Abstract

Cbls are RING ubiquitin ligases that attenuate receptor tyrosine kinase (RTK) signal transduction. Cbl ubiquitination activity is stimulated by phosphorylation of a linker helix region (LHR) tyrosine residue. To elucidate the mechanism of activation, we determined the structures of human CBL, a CBL−substrate peptide complex and a phosphorylated-Tyr371-CBL−E2−substrate peptide complex, and we compared them with the known structure of a CBL−E2−substrate peptide complex. Structural and biochemical analyses show that CBL adopts an autoinhibited RING conformation, where the RING's E2-binding surface associates with CBL to reduce E2 affinity. Tyr371 phosphorylation activates CBL by inducing LHR conformational changes that eliminate autoinhibition, flip the RING domain and E2 into proximity of the substrate-binding site and transform the RING domain into an enhanced E2-binding module. This activation is required for RTK ubiquitination. Our results present a mechanism for regulation of c-Cbl's activity by autoinhibition and phosphorylation-induced activation.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Huang, Professor Danny and Hock, Dr Andreas and Sibbet, Dr Gary and Dou, Miss Hao and Vousden, Karen and Buetow, Dr Lori
• Authors: Dou, H., Buetow, L., Hock, A., Sibbet, G.J., Vousden, K.H., and Huang, D.T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Structural and Molecular Biology
• ISSN: 1545-9993
• ISSN (Online): 1545-9985
• Published Online: 22 January 2012