Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mu...

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Bibliographic Details
Published in:PloS one 2015-06, Vol.10 (6), p.e0130610-e0130610
Main Authors: Arregi, Igor, Falces, Jorge, Olazabal-Herrero, Anne, Alonso-Mariño, Marián, Taneva, Stefka G, Rodríguez, José A, Urbaneja, María A, Bañuelos, Sonia
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Acute myeloid leukemia
Affinity
Anisotropy
Antifungal agents
Biochemistry
Biosynthesis
Calorimetry
Cell growth
Cell Nucleolus - metabolism
Circular Dichroism
Cytoplasm
Cytoplasm - metabolism
Exportin 1 Protein
Exports
Fluorescence
Fluorescence Polarization
HEK293 Cells
HeLa Cells
Humans
Karyopherins - chemistry
Karyopherins - genetics
Karyopherins - metabolism
Leukemia
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Molecular biology
Molecular chains
Mutants
Mutation
Myeloid leukemia
Nuclear Export Signals
Nuclear Proteins - chemistry
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Nuclear transport
Nucleoli
Nucleophosmin
Phosphorylation
Physical anthropology
Physiology
Protein Binding
Protein Structure, Tertiary
Proteins
Receptors, Cytoplasmic and Nuclear - chemistry
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - metabolism
Recognition
Recombinant Proteins - biosynthesis
Recombinant Proteins - chemistry
Recombinant Proteins - isolation & purification
Thermodynamics
Titration
Titration calorimetry
Traffic
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Description
Summary:Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0130610