Figure 1.
Structure and mutliple functions of NPM1wt. (A) Structure of NPM1wt and mutant NPM1 (NPM1mut) for comparison. NPM1wt and NPM1mut share the same structure, only differing in the very last portion of the C terminus. The hydrophobic N terminus contains 2 weak leucine-rich nuclear export signals (NESs) and a self-oligomerization core responsible for the formation of NPM1 pentamers. The N terminus also acts as a chaperone by preventing protein misfolding in the nucleolus. The central portion of NPM1wt is highly disordered and acidic because it contains two 10- to 20-aa stretches of aspartic and glutamic acid residues whose negative charge is involved in binding of NPM1wt to histones. The central region also contains a bipartite NLS driving the protein from the cytoplasm to the nucleoplasm. The C-terminal basic domain of NPM1wt mediates binding to nucleic acids and TP53. The very last portion of the NPM1wt C terminus, with its highly conserved W288 and W290, forms a globular structure consisting of a 3-helix bundle, which is responsible for its nucleolar localization signal (NoLS). Compared with NPM1wt, the C terminus of NPM1mut loses W288 and W290 (or W290 alone) and gains a new NES. (B) Summary of the multiple functions of NPM1wt. NPM1wt inhibits centrosome duplication (1). During the cell cycle, NPM1wt is released from the centrosome to allow its duplication and the formation of the mitotic spindle. With its predominant nucleolar localization and the ability to bind rRNA and ribosomal proteins, NPM1wt cooperates in ribosome biogenesis (2). NPM1wt is also a histone chaperone (3) with the ability to bind core and linker histones and to regulate the formation of perinucleolar heterochromatin. It is also involved in DNA repair (4); NPM1wt binds to TP53, enhancing its stability and transcriptional activity, as well as to APE1, regulating its endonuclease activity depending on the type of DNA damage. All of the above functions have been reviewed extensively.6-9 More details regarding the involvement of NPM1wt in other recently reported functions, such as 2′-O-methylation of rRNA (5) and LLPS in the nucleolus (6) are provided in the text. (C) Schematic representation of NPM1wt behavior upon nucleolar stress. Nucleolar stress through the inhibition of RNA polymerase I results in the spread of NPM1wt from the nucleolus to the nucleoplasm. There, NPM1wt can bind and inhibit HDM2, a protein with E3 ligase activity that promotes TP53 degradation through the proteasome. HDM2 inhibition results in increased levels of TP53, cell cycle arrest, and apoptosis. FBL, fibrillarin; NIPBL, nipped-B-like protein; snoRNA, small nucleolar RNA.

Structure and mutliple functions of NPM1wt. (A) Structure of NPM1wt and mutant NPM1 (NPM1mut) for comparison. NPM1wt and NPM1mut share the same structure, only differing in the very last portion of the C terminus. The hydrophobic N terminus contains 2 weak leucine-rich nuclear export signals (NESs) and a self-oligomerization core responsible for the formation of NPM1 pentamers. The N terminus also acts as a chaperone by preventing protein misfolding in the nucleolus. The central portion of NPM1wt is highly disordered and acidic because it contains two 10- to 20-aa stretches of aspartic and glutamic acid residues whose negative charge is involved in binding of NPM1wt to histones. The central region also contains a bipartite NLS driving the protein from the cytoplasm to the nucleoplasm. The C-terminal basic domain of NPM1wt mediates binding to nucleic acids and TP53. The very last portion of the NPM1wt C terminus, with its highly conserved W288 and W290, forms a globular structure consisting of a 3-helix bundle, which is responsible for its nucleolar localization signal (NoLS). Compared with NPM1wt, the C terminus of NPM1mut loses W288 and W290 (or W290 alone) and gains a new NES. (B) Summary of the multiple functions of NPM1wt. NPM1wt inhibits centrosome duplication (1). During the cell cycle, NPM1wt is released from the centrosome to allow its duplication and the formation of the mitotic spindle. With its predominant nucleolar localization and the ability to bind rRNA and ribosomal proteins, NPM1wt cooperates in ribosome biogenesis (2). NPM1wt is also a histone chaperone (3) with the ability to bind core and linker histones and to regulate the formation of perinucleolar heterochromatin. It is also involved in DNA repair (4); NPM1wt binds to TP53, enhancing its stability and transcriptional activity, as well as to APE1, regulating its endonuclease activity depending on the type of DNA damage. All of the above functions have been reviewed extensively.6-9  More details regarding the involvement of NPM1wt in other recently reported functions, such as 2′-O-methylation of rRNA (5) and LLPS in the nucleolus (6) are provided in the text. (C) Schematic representation of NPM1wt behavior upon nucleolar stress. Nucleolar stress through the inhibition of RNA polymerase I results in the spread of NPM1wt from the nucleolus to the nucleoplasm. There, NPM1wt can bind and inhibit HDM2, a protein with E3 ligase activity that promotes TP53 degradation through the proteasome. HDM2 inhibition results in increased levels of TP53, cell cycle arrest, and apoptosis. FBL, fibrillarin; NIPBL, nipped-B-like protein; snoRNA, small nucleolar RNA.

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