Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein

Biomolecules. 2020 Jan 6;10(1):90. doi: 10.3390/biom10010090.

Abstract

The N-Myc downstream-regulated gene (NDRG) family belongs to the α/β-hydrolase fold and is known to exert various physiologic functions in cell proliferation, differentiation, and hypoxia-induced cancer metabolism. In particular, NDRG3 is closely related to proliferation and migration of prostate cancer cells, and recent studies reported its implication in lactate-triggered hypoxia responses or tumorigenesis. However, the underlying mechanism for the functions of NDRG3 remains unclear. Here, we report the crystal structure of human NDRG3 at 2.2 Å resolution, with six molecules in an asymmetric unit. While NDRG3 adopts the α/β-hydrolase fold, complete substitution of the canonical catalytic triad residues to non-reactive residues and steric hindrance around the pseudo-active site seem to disable the α/β-hydrolase activity. While NDRG3 shares a high similarity to NDRG2 in terms of amino acid sequence and structure, NDRG3 exhibited remarkable structural differences in a flexible loop corresponding to helix α6 of NDRG2 that is responsible for tumor suppression. Thus, this flexible loop region seems to play a distinct role in oncogenic progression induced by NDRG3. Collectively, our studies could provide structural and biophysical insights into the molecular characteristics of NDRG3.

Keywords: NDRG3; crystal structure; unfolded helix; α/β-hydrolase fold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Nerve Tissue Proteins / genetics
  • Prostatic Neoplasms / genetics
  • Protein Conformation
  • Tumor Suppressor Proteins / metabolism
  • X-Ray Diffraction / methods

Substances

  • Intracellular Signaling Peptides and Proteins
  • NDRG3 protein, human
  • Nerve Tissue Proteins
  • Tumor Suppressor Proteins