Abstract
Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.
Highlights
Nucleophosmin (NPM1, known as B23) is an abundant and multifunctional phosphoprotein mainly found in nucleoli [1]
Since p14ARF is one of NPM1 interactors that are displaced to the cytoplasm in NPM1-mutated acute myeloid leukemia (AML) [68] and given that p14ARF is often altered in several cancers [117], the NPM1 surface that interacts with p14ARF has been proposed as a target for interfering small molecules to be used in the treatment of AML or possibly other cancers [118]
NPM1 is a protein endowed with many crucial functions that are exerted in different cell compartments through the interaction with protein and nucleic acids partners
Summary
Nucleophosmin (NPM1, known as B23) is an abundant and multifunctional phosphoprotein mainly found in nucleoli [1]. In between the A3 acidic region and the C-terminal domain (CTD), NPM1 contains a markedly basic segment of over 50 residues that have been suggested to facilitate NPM1 interactions with nucleic acids, working in concert with the C-terminal domain (CTD, Figure 1B) [17,36,37] The latter consists of a right-handed three-helix bundle that is stabilized by a hydrophobic core mainly formed by five conserved aromatic residues (F268, Y271, F276, W288, W290). The region encompassing the two tryptophan residues W288 and W290, within the CTD, has been ascribed to form an atypical nucleolar localization signal (NoLS), specific to NPM1 [39,40] This domain is unique to NPM1 as compared to other members in the nucleophosmin/nucleoplasmin family [39] and its deletion, or alterations at the two key tryptophan residues that cause domain unfolding, compromise both nucleic acid binding and nucleolar localization [38,41,42] (Figure 1B). As will be described such mutations are typically found in acute myeloid leukemia (AML) patients (Figure 1C)
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