Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases.
Ubiquitin-protein ligases (E3s) regulate diverse cellular processes by mediating protein ubiquitination. The c-Cbl proto-oncogene is a RING family E3 that recognizes activated receptor tyrosine kinases, promotes their ubiquitination by a ubiquitin-conjugating enzyme (E2) and terminates signaling. The crystal structure of c-Cbl bound to a cognate E2 and a kinase peptide shows how the RING domain recruits the E2. A comparison with a HECT family E3-E2 complex indicates that a common E2 motif is recognized by the two E3 families. The structure reveals a rigid coupling between the peptide binding and the E2 binding domains and a conserved surface channel leading from the peptide to the E2 active site, suggesting that RING E3s may function as scaffolds that position the substrate and the E2 optimally for ubiquitin transfer.
Zheng
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N
Cellular Biochemistry and Biophysics Program, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Wang
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Jeffrey
P D
PD
Pavletich
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NP
D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D004330:Drosophila; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D013329:Structure-Activity Relationship; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases
C000715470:MAS1 protein, human; D046911:Macromolecular Substances; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C079437:UBE2L3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C067419:CBL protein, human