Structure of the p210Bcr-Abl fusion protein and mechanisms of leukemogenesis.
Some of the important functional domains on the Bcr and Abl moieties are shown: in Bcr, the dimerization domain (DD), the Y177 autophosphorylation site for adaptor protein binding, the phosphoserine/phosphothreonine-rich sequences(P-S/T) on the SH2-binding domain, and the region homologous to Rho guanidine nucleotide exchange factors (Rho-GEF); in Abl, the Src-homology SH2 and SH3 regulatory domains, the tyrosine kinase (SH1) domain where binding to ATP and substrate takes place, 1 of the 3 nuclear localization signal (NLS), 1 of 3 DNA-binding, a nuclear export signal (NES) and 1 of 2 actin-binding domains. Disruption of the tightly regulated tyrosine kinase activity of Abl by dimerization of the protein effected by BCR first exon sequences (indicated by the arrow) results cellular responses that characterize the leukemic phenotype.
