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

DOI: 10.1038/nsmb.2231
PMID: 22266821

Authors: Hao Dou (Beatson Institute for Cancer Research) , Lori Buetow (Beatson Institute for Cancer Research) , Andreas Hock (The Beatson Institute for Cancer Research, Glasgow) , Gary J Sibbet (The Beatson Institute for Cancer Research, Glasgow) , Karen H Vousden (The Beatson Institute for Cancer Research, Glasgow) , Danny Huang (Beatson Institute for Cancer Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 19 (2) , PAGES 184 - 192

State: Published (Approved)
Published: January 2012
Diamond Proposal Number(s): 6683 , 1229

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.

Journal Keywords: X-Ray; Humans; Models; Molecular; Phosphorylation; Protein; Post-Translational; Proto-Oncogene Proteins c-cbl

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF (ID14-1 beamline)