Computational analysis of the quaternary structural changes induced by point mutations in human UDP-glucose dehydrogenase.
UDP-glucose dehydrogenase (UGDH) is an enzyme catalyzing the conversion of UDP-glucose to UDP-glucuronic acid. Site-directed mutagenesis studies have revealed that human UGDH (hUGDH) has distinct oligomeric states that vary with different point mutations. In this study we have investigated how the changes in the oligomer-forming propensity may be involved in the thermal motion of wild-type hUGDH and its mutants, using normal mode analysis (NMA). Our results show that the perturbation caused by the mutation of a residue at a considerably distant location from the oligomeric interfaces is preferentially distributed throughout specific sites, especially the large flexible regions in the hUGDH structure, thereby changing the motional fluctuation pattern at the oligomeric interfaces. A large-magnitude cooperative motion at the oligomeric interfaces is a critical factor in interfering with the hexamer formation of the enzyme. In particular, structural stability at the dimeric interface is necessary to retain the hexameric structure of hUGDH.
Department of Physiology and Research Institute for Biomacromolecules, University of Ulsan College of Medicine. Seoul 138-736, South Korea.
Hui Sun
HS
Lee
Young Jin
YJ
Son
Seon Ha
SH
Chong
Ji Young
JY
Bae
Chae Hun
CH
Leem
Yeon Jin
YJ
Jang
Han
H
Choe
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D021122:Protein Subunits; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000737:chemistry* / Q000235:genetics*
D021122:Protein Subunits; D014533:Uridine Diphosphate Glucose Dehydrogenase