Nucleophosmin in Its Interaction with Ligands

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.

TLR4/MD‑2 is a receptor for extracellular nucleophosmin 1

“…NPM1 belongs to a chaperone family, which comprises multiple major functional members (NPM1, NPM2 and NPM3) in the intracellular space ( 27 ). Residues in the N-terminal domain (Met9 to Asp122) are highly conserved and essential for its oligomerization and interactions with other proteins ( 8 ).…”

PhosIDP: a web tool to visualize the location of phosphorylation sites in disordered regions

“…The potential of our server to highlight the role phosphorylation could play in structural transitions is demonstrated with human nucleophosmin, which (in common with CIRBP) is classified as a core protein in regard to formation of membraneless organelles 14 . Nucleophosmin shuttles between the nucleus and cytoplasm, undertaking multiple roles 18 . The current focus is on how prediction of structured and unstructured regions in the phosIDP server, and the presence of phosphorylation sites, correlates with segments for which structural flexibility is known to correlate with function.…”

Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

“…The lower functional consensus of short loops in AML indicates that proteins mutated in AML play roles in a wide range of biological processes as GO classifications of the functions in AML short loops tend to be general and less specific (Figure 1 and Supplementary Table S9 ) including metabolic processes, signal transduction and gene expression. For example, nucleophosmin (NPM1) is mutated in 50–60% of AML patients with normal karyotype ( 75 , 76 ) and the interaction between NPM1 and cellular tumour antigen p53 (TP53) ( 77 ) makes short loop interactions with 25 different proteins such as cell cycle related proteins (CDKN2A, RB1), ribosomal proteins (RPL6, RPS16, RPS13), histone binding (EP300, RBBP4), actin binding (FLNA) and ubiquitin (OTUB1) ( 78 ). Therefore, the results of the short loop network motif profiling of the leukaemia-specific PPINs and the functions affected by mutations not only reflect the complexity of the diseases, but also show that mutations in AML affect a wider range of cellular functions than those affected by mutations in the other three leukaemias or in other cancers (pan-cancer analysis).…”