Crystal structure of the human N-Myc downstream-regulated gene 2 protein provides insight into its role as a tumor suppressor.
Considerable attention has recently been paid to the N-Myc downstream-regulated gene (NDRG) family because of its potential as a tumor suppressor in many human cancers. Primary amino acid sequence information suggests that the NDRG family proteins may belong to the α/β-hydrolase (ABH) superfamily; however, their functional role has not yet been determined. Here, we present the crystal structures of the human and mouse NDRG2 proteins determined at 2.0 and 1.7 Å resolution, respectively. Both NDRG2 proteins show remarkable structural similarity to the ABH superfamily, despite limited sequence similarity. Structural analysis suggests that NDRG2 is a nonenzymatic member of the ABH superfamily, because it lacks the catalytic signature residues and has an occluded substrate-binding site. Several conserved structural features suggest NDRG may be involved in molecular interactions. Mutagenesis data based on the structural analysis support a crucial role for helix α6 in the suppression of TCF/β-catenin signaling in the tumorigenesis of human colorectal cancer, via a molecular interaction.
Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
Jungwon
J
Hwang
Yoonjeong
Y
Kim
Ho Bum
HB
Kang
Lukasz
L
Jaroszewski
Ashley M
AM
Deacon
Hwiseop
H
Lee
Won-Chan
WC
Choi
Kyung-Jin
KJ
Kim
Cheol-Hee
CH
Kim
Beom Sik
BS
Kang
Jie-Oh
JO
Lee
Tae-Kwang
TK
Oh
Jae Wha
JW
Kim
Ian A
IA
Wilson
Myung Hee
MH
Kim
D000595:Amino Acid Sequence; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism*
C466228:NDRG2 protein, human; D025521:Tumor Suppressor Proteins
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