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Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members

Marcos, E and Crehuet, R and Bahar, I (2011) Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members. PLoS Computational Biology, 7 (9). ISSN 1553-734X

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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. It also highlights the significance of the particular quaternary design in selectively determining the oligomer dynamics congruent with required ligand-binding and allosteric activities. © 2011 Marcos et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Marcos, E
Crehuet, R
Bahar, Ibahar@pitt.eduBAHAR
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorGilson, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 September 2011
Date Type: Publication
Journal or Publication Title: PLoS Computational Biology
Volume: 7
Number: 9
DOI or Unique Handle: 10.1371/journal.pcbi.1002201
Schools and Programs: School of Medicine > Computational and Systems Biology
Refereed: Yes
ISSN: 1553-734X
MeSH Headings: Allosteric Regulation; Allosteric Site; Amino Acids--metabolism; Catalytic Domain; Computational Biology; Computer Simulation; Dimerization; Models, Molecular; Molecular Dynamics Simulation; Nucleoside-Phosphate Kinase--chemistry; Nucleoside-Phosphate Kinase--metabolism; Phosphotransferases--chemistry; Phosphotransferases--metabolism; Phosphotransferases (Carboxyl Group Acceptor)--chemistry; Phosphotransferases (Carboxyl Group Acceptor)--metabolism; Protein Binding; Protein Multimerization; Protein Structure, Quaternary; Substrate Specificity; Thermodynamics
Other ID: NLM PMC3182869
PubMed Central ID: PMC3182869
PubMed ID: 21980279
Date Deposited: 05 Sep 2012 20:05
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/13901

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