Type C mutation of nucleophosmin 1 acute myeloid leukemia: Consequences of intrinsic disorder.
Acute myeloid leukemia
Aggregation
Intrinsically disordered regions
Wide-Angle X-ray Scattering
Journal
Biochimica et biophysica acta. General subjects
ISSN: 1872-8006
Titre abrégé: Biochim Biophys Acta Gen Subj
Pays: Netherlands
ID NLM: 101731726
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
03
02
2022
revised:
09
04
2022
accepted:
13
05
2022
pubmed:
22
5
2022
medline:
3
6
2022
entrez:
21
5
2022
Statut:
ppublish
Résumé
Nucleophosmin 1 (NPM1) protein is a multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML). AML mutations cause the unfolding of the C-terminal domain (CTD) and the protein delocalizing in the cytosol (NPM1c+). Marked aggregation endowed with an amyloid character was assessed as consequences of mutations. Herein we analyzed the effects of type C mutation on two protein regions: i) a N-terminal extended version of the CTD, named Cterm_mutC and ii) a shorter polypeptide including the sequences of the second and third helices of the CTD, named H2_mutC. Both demonstrated able to self-assembly with different kinetics and conformational intermediates and to provide fibers presenting large flexible regions. The present study adds a new piece of knowledge to the effects of AML-mutations on structural biology of Nucleophosmin 1, that could be exploited in therapeutic interventions targeting selectively NPMc+.
Sections du résumé
BACKGROUND
Nucleophosmin 1 (NPM1) protein is a multifunctional nucleolar chaperone and its gene is the most frequently mutated in Acute Myeloid Leukemia (AML). AML mutations cause the unfolding of the C-terminal domain (CTD) and the protein delocalizing in the cytosol (NPM1c+). Marked aggregation endowed with an amyloid character was assessed as consequences of mutations.
SCOPE
Herein we analyzed the effects of type C mutation on two protein regions: i) a N-terminal extended version of the CTD, named Cterm_mutC and ii) a shorter polypeptide including the sequences of the second and third helices of the CTD, named H2_mutC.
MAJOR CONCLUSIONS
Both demonstrated able to self-assembly with different kinetics and conformational intermediates and to provide fibers presenting large flexible regions.
GENERAL SIGNIFICANCE
The present study adds a new piece of knowledge to the effects of AML-mutations on structural biology of Nucleophosmin 1, that could be exploited in therapeutic interventions targeting selectively NPMc+.
Identifiants
pubmed: 35597503
pii: S0304-4165(22)00091-5
doi: 10.1016/j.bbagen.2022.130173
pii:
doi:
Substances chimiques
Amyloidogenic Proteins
0
NPM1 protein, human
0
Nuclear Proteins
0
Nucleophosmin
117896-08-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
130173Informations de copyright
Copyright © 2022 Elsevier B.V. All rights reserved.