Molecular structure of nucleophosmin (NPM), anaplastic lymphoma kinase (ALK), and ALK fusion proteins.

The NPM molecule consists of an oligomerization domain (residues 1-83), a metal-binding domain (MB; residues 104-115), 2 acidic amino acid clusters (AC; residues 120-132 and 161-188) that function as acceptor regions for nucleolar targeting signals,82 and 2 nuclear localization signals (NLS). The oligomerization domain was defined by means of deletion mutants.81 The ALK protein is a transmembrane tyrosine kinase receptor containing a transmembrane domain (TM) and a tyrosine kinase domain (TKD) in the N-terminal part of the intracytoplasmic tail. In the NPM-ALK fusion protein, the extracellular and transmembrane domains of ALK are replaced by the oligomerization domain of NPM (in approximately 75%) or of other proteins (X), schematically represented in Figure 7. The fused part of NPM contains, in addition to the oligomerization domain, the metal-binding region. The fusion point is at codon 117. N indicates amino terminal; C, carboxy terminal.