Featured Article - April 2011
Short description: While the NDRG family has been implicated in a number of diseases and cancers, the molecular function of these factors remains unclear. The structures of NDRG2 reveal unusual features that give insight into these functions.
Understanding how potential tumor suppressors function is one key to being able to tackle tumorigenesis. The conserved N-Myc downstream-regulated gene (NDRG) family has gained interest as they are repressed by the Myc oncogene and have been argued to have tumor-suppressive and anti-metastatic functions. In addition, NDRG1 has been linked to disease states including demyelinating neuropathy. Despite this, little is known about the molecular function and targets of the NDRG family, though on the basis of their sequences they have been proposed to resemble the α/β hydrolase (ABH) superfamily. Kim (Korea Research Institute of Bioscience and Biotechnology (KRIBB)), Wilson and colleagues (Joint Center for Structural Genomics (PSI JCSG)) have now solved the structures of both the mouse and the human NDRG2. Solving the mouse structure in this case facilitated finding the structure of the human ortholog. The structures turn out to resemble the ABH fold, as expected, and they also carry a small 'cap' domain. However, there are differences from other ABH fold proteins that are functionally telling: the catalytic triad is mutated, and residues occlude what would be the active site in enzymatically active α/β hydrolases. These changes are conserved across most NDRG family members, indicating that they act non-enzymatically, perhaps in binding roles. Indeed, the presented NDRG2 structures all carry a helix (α6, circled in blue in the figure) in the cap domain that, in contrast to ABH superfamily members, exposes a hydrophobic face to solvent. The authors followed up on this red flag, finding that deletion or point mutation of this helix affects its previously described interaction with β-catenin, which is involved in a key signaling pathway in development and disease. Helix α6 also has an impact on TCF and β-catenin signaling, as assessed using a reporter system in SW620 colon cancer cells. In addition, target genes of this signaling pathway, including Cycin D1 and fibronectin, were repressed by expression of NDRG2, but this did not occur in a mutant in which this exposed helix was targeted. In summary, this work provides a first structural glimpse of the NDRG family and, given the level of conservation across the family, will allow further work to elucidate the molecular function of both NDRG2 and its relatives.
Hwang et al. Crystal structure of human NDRG2 protein provides insight into its role as a tumor suppressor.
J. Biol. Chem. (18 January 2011). doi:10.1074/jbc.M110.170803