2Y1M

Structure of native c-Cbl

Summary for 2Y1M

• Entry DOI: 10.2210/pdb2y1m/pdb
• Related: 1B47 1FBV 1YVH 2CBL 2Y1N 4A49 4A4B 4A4C
• Descriptor: E3 UBIQUITIN-PROTEIN LIGASE, ZINC ION, CALCIUM ION, ... (4 entities in total)
• Functional Keywords: ligase, ubiquitin ring e3 ligase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: P22681
• Total number of polymer chains: 6
• Total formula weight: 270597.55

Authors

Dou, H.,Sibbet, G.J.,Huang, D.T. (deposition date: 2010-12-08, release date: 2012-01-18, Last modification date: 2023-12-20)

Primary citation

Dou, H.,Buetow, L.,Hock, A.,Sibbet, G.J.,Vousden, K.H.,Huang, D.T.
Structural Basis for Autoinhibition and Phosphorylation-Dependent Activation of C-Cbl.
Nat.Struct.Mol.Biol., 19:184-, 2012

PubMed 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.

PubMed: 22266821
DOI: 10.1038/NSMB.2231

Experimental method

X-RAY DIFFRACTION (2.67 Å)