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Structural and Biophysical Analyses of Human N-Myc Downstream-Regulated Gene 3 (NDRG3) Protein
Kyung Rok Kim1, Kyung A Kim1, Joon Sung Park1
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
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.
Insights
The N-Myc downstream-regulated gene 3 (NDRG3) protein, despite its structural similarity to enzymes, lacks hydrolase activity. Unique structural features in NDRG3 suggest a role in cancer progression, distinct from NDRG2
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Research
Background:
- The N-Myc downstream-regulated gene (NDRG) family plays roles in cell processes and cancer.
- NDRG3 is implicated in prostate cancer proliferation, migration, and hypoxia responses.
- The precise mechanism of NDRG3 function remains largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanism of NDRG3 function.
- To determine the crystal structure of human NDRG3.
- To investigate the structural basis for NDRG3's role in cancer.
Main Methods:
- X-ray crystallography to determine the 3D structure of human NDRG3 at 2.2 Å resolution.
- Structural analysis comparing NDRG3 to other NDRG family members, particularly NDRG2.
- Biophysical analysis to assess enzymatic activity.
Main Results:
- The crystal structure of human NDRG3 was determined, revealing an α/β-hydrolase fold.
- NDRG3 possesses non-reactive residues in its active site, disabling typical hydrolase activity.
- Significant structural differences were observed in a flexible loop region compared to NDRG2, which is involved in tumor suppression.
Conclusions:
- NDRG3's structure suggests it functions independently of canonical α/β-hydrolase activity.
- The unique flexible loop in NDRG3 likely contributes to its distinct role in oncogenic progression.
- These findings provide crucial structural insights into NDRG3's molecular characteristics and potential involvement in cancer.
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