Autoinhibition of c-Abl.
Despite years of investigation, the molecular mechanism responsible for regulation of the c-Abl tyrosine kinase has remained elusive. We now report inhibition of the catalytic activity of purified c-Abl in vitro, demonstrating that regulation is an intrinsic property of the molecule. We show that the interaction of the N-terminal 80 residues with the rest of the protein mediates autoregulation. This N-terminal "cap" is required to achieve and maintain inhibition, and its loss turns c-Abl into an oncogenic protein and contributes to deregulation of BCR-Abl.
Pluk
Helma
H
Developmental Biology Programme, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Dorey
Karel
K
Superti-Furga
Giulio
G
D000595:Amino Acid Sequence; D002460:Cell Line; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014162:Transfection
D011993:Recombinant Fusion Proteins; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl