Nucleophosmin (NPM), also known as nucleolar phosphoprotein B23 or numatrin, is a protein that in humans is encoded by the NPM1 gene.

NPM1 was first discovered as a nucleolar phosphoprotein in rat liver cells and Novikoff hepatoma ascites cells. It was named B23 as it was the 23rd spot in the B section of the 2-D gel where spots were numbered in the order of decreasing mobility. It was named numatrin independently by another group as it was found to be tightly associated with the nuclear matrix and its expression was induced upon mitogenic signals in human B lymphocytes. At around the same time, the Xenopus NO38 was discovered and was found to be homologous to Xenopus Nucleoplasmin and rat B23.

In humans, the NPM1 gene is located on the long arm of chromosome 5 (5q35). The gene spans 23 kb and contains 12 exons. Three transcript variants have been described. The longest isoform (294 amino acids long), encoded by transcript variant 1, is the major and the most well studied isoform of Nucleophosmin. Transcript variant 2 is produced by skipping an in-frame exon (exon 8) to produce an isoform that is 265 amino acids long. However, this isoform is not well characterized and its functions and expression pattern is not well understood. Transcript variant 3 is produced by using an alternate exon (exon 10) which results in an isoform 259 amino acids long with a different C-terminal sequence. The isoforms 1 and 3 of human NPM1 are B23.1 and B23.2 respectively in rat. The isoform 1 is localized to the nucleolus as is reported for rat B23.1 whereas the isoform 3 (B23.2) is nucleoplasmic or cytoplasmic in localization and is expressed at relatively lower levels as compared to isoform 1 in normal rat tissues and in HeLa cells. Both isoforms 1 and 3 have been shown to stimulate the replication of adenoviral DNA complexed with viral basic proteins.

The NPM1 protein can be divided into several domains with sequence motifs that are conserved across nucleoplasmin family and have important and distinct functions. The N-terminal core domain, the acidic stretches, basic domain and the aromatic nucleic acid domain make up the NPM1 protein. Further, sequence motifs such as the nuclear export signals (NES), nuclear localization signals (NLS) and the nucleolar localization signals (NoLS) are critical for the localization of NPM1 to the nucleolus as well as its nucleo-cytoplasmic shuttling required for its diverse array of functions.

The N-terminal domain also known as the core domain (residues 1-119 of human NPM1) is the most conserved domain among the NPM family proteins. This domain folds into a distinct structure that is protease resistant and is responsible for the oligomerization and chaperone activity of these proteins. It contains several hydrophobic residues that are highly conserved (~80%) among NPM proteins. The crystal structure of NPM1 core domain (residues 9-122) shows that this domain folds into an eight stranded β-barrel with jelly roll topology forming a wedge shaped hydrophobic core that fits snugly to form a pentamer through hydrophobic interactions between the monomeric subunits. Two pentameric complexes align in a head to head fashion to form the decameric structure. A comparison between the crystal structure of human NPM1 and that of the core domains of Xenopus NO38, Xenopus Nucleoplasmin and Drosophila Nucleoplasmin like protein (dNLP) show that both the monomeric and pentameric structures are highly similar among all the NPM family proteins. The human NPM1 core domain (residues 15-118) shares a sequence identity of 80%, 51% and 29% with Xenopus NO38, Nucleoplasmin and Drosophila NLP cores respectively. All of them form the same β barrel structure with jelly roll topology.

NPM1 was speculated to be a hexamer under native conditions since it was found to have a molecular weight of 230–255 kDa calculated by gel filtration chromatography and sedimentation analyses. However, the crystal structure of the NPM1 core clearly shows that it is a pentamer. The pentamer-pentamer interface consists of several water molecules involved in hydrogen bonding between the two pentamers. Moreover, ten charge based interactions between the Asp of the highly conserved AKDE loop and Lys82 give additional stability. Comparison of dNLP and Nucleoplasmin structures has revealed that formation of the decamer might be facilitated by histone binding. The H2A-H2B dimer may bind to the lateral surface of the NPM1 decamer. Furthermore, comparison of the crystal structures of human NPM1 and Xenopus NO38 reveals structural plasticity in the pentamer-pentamer interface. When one of the pentamers of human NPM1 and Xenopus NO38 are superimposed, there is a large rotational offset (~20°) between the other pentamers. Further, the direction of the rotational offsets are opposite for human NPM1 and Xenopus NO38 when compared to Xenopus Nucleoplasmin core structure. The significance of this structural plasticity is not well understood, however, it may have a significance in the chaperone function of NPM1.

NPM1 is associated with nucleolar ribonucleoprotein structures and binds single-stranded and double-stranded nucleic acids, but it binds preferentially G-quadruplex forming nucleic acids. It is involved in the biogenesis of ribosomes and may assist small basic proteins in their transport to the nucleolus. Its regulation through SUMOylation (by SENP3 and SENP5) is another facet of the protein's regulation and cellular functions.

It is located in the nucleolus, but it can be translocated to the nucleoplasm in case of serum starvation or treatment with anticancer drugs. The protein was identified as a phosphoprotein. However, later other post-translational modifications for NPM1 were identified including acetylation and SUMOylation.