Type C mutation of nucleophosmin 1 acute myeloid leukemia: Consequences of intrinsic disorder

Biochim Biophys Acta Gen Subj. 2022 Aug;1866(8):130173. doi: 10.1016/j.bbagen.2022.130173. Epub 2022 May 18.

Abstract

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+.

Keywords: Acute myeloid leukemia; Aggregation; Intrinsically disordered regions; Wide-Angle X-ray Scattering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidogenic Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Mutation
  • Nuclear Proteins / genetics
  • Nucleophosmin* / genetics
  • Nucleophosmin* / metabolism

Substances

  • Amyloidogenic Proteins
  • NPM1 protein, human
  • Nuclear Proteins
  • Nucleophosmin