changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members动力学变化在寡聚化调节衬底绑定和家庭成员在氨基酸激酶变构效应.pdfVIP

Changes in Dynamics upon Oligomerization Regulate Substrate Binding and Allostery in Amino Acid Kinase Family Members 1 1 2 Enrique Marcos , Ramon Crehuet *, Ivet Bahar * 1 Department of Biological Chemistry and Molecular Modelling, IQAC-CSIC, Barcelona, Spain, 2 Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Abstract Oligomerization is a functional requirement for many proteins. The interfacial interactions and the overall packing geometry of the individual monomers are viewed as important determinants of the thermodynamic stability and allosteric regulation of oligomers. The present study focuses on the role of the interfacial interactions and overall contact topology in the dynamic features acquired in the oligomeric state. To this aim, the collective dynamics of enzymes belonging to the amino acid kinase family both in dimeric and hexameric forms are examined by means of an elastic network model, and the softest collective motions (i.e., lowest frequency or global modes of motions) favored by the overall architecture are analyzed. Notably, the lowest-frequency modes accessible to the individual subunits in the absence of multimerization are conserved to a large extent in the oligomer, suggesting that the oligomer takes advantage of the intrinsic dynamics of the individual monomers. At the same time, oligomerization stiffens the interfacial regions of the monomers and confers new cooperative modes that exploit the rigid-body translational and rotational degrees of freedom of the intact monomers. The present study sheds light on the mechanism of cooperative inhibition of hexameric N-acetyl-L-glutamate kinase by arginine and on the allosteric regulation of UMP kinases