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Changes in Dynamics upon Oligomerization Regulate Substrate Binding and Allostery in Amino Acid Kinase Family Members

By Enrique Marcos, Ramon Crehuet and Ivet Bahar

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3182869
Provided by: PubMed Central

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Citations

  1. (2002). A coarse-grained normal mode approach for macromolecules: An efficient implementation and application to Ca2+-ATPase.
  2. (2009). A comparative analysis of the equilibrium dynamics of a designed protein inferred from NMR, X-ray, and computations.
  3. (2007). A hierarchy of timescales in protein dynamics is linked to enzyme catalysis.
  4. (2007). A novel two-domain architecture within the amino acid kinase enzyme family revealed by the crystal structure of Escherichia coli glutamate 5-kinase.
  5. (2003). Allosteric changes in protein structure computed by a simple mechanical model: Hemoglobin T ,-. R2 transition.
  6. (2005). Allosteric mechanisms of signal transduction.
  7. (2008). Allosteric regulation and catalysis emerge via a common route.
  8. (2009). Allosteric Transitions in Biological Nanomachines are Described by Robust Normal Modes of Elastic Networks.
  9. (2009). Allosteric Transitions of Supramolecular Systems Explored by Network Models: Application to Chaperonin GroEL.
  10. (2005). Allostery in a coarse-grained model of protein dynamics.
  11. (1996). Analysis of the low frequency normal modes of the T-state of aspartate transcarbamylase.
  12. (2006). Anisotropic network model: systematic evaluation and a new web interface.
  13. (2001). Anisotropy of fluctuation dynamics of proteins with an elastic network model.
  14. (2008). Antenna domain mobility and enzymatic reaction of L-rhamnulose-1-phosphate aldolase.
  15. (1991). Application of linear free-energy relations to protein conformational changes: the quaternary structural change of hemoglobin.
  16. (2011). Applying molecular dynamics simulations to identify rarely sampled ligand-bound conformational states of undecaprenyl pyrophosphate synthase, an antibacterial target.
  17. (2008). Basis of arginine sensitivity of microbial N-acetyl-L-glutamate kinases: Mutagenesis and protein engineering study with the Pseudomonas aeruginosa and Escherichia coli enzymes.
  18. (1999). Carbamate kinase: New structural machinery for making carbamoyl phosphate, the common precursor of pyrimidines and arginine.
  19. (1994). Cavities and packing at protein interfaces.
  20. (2008). Close correspondence between the motions from principal component analysis of multiple HIV-1 protease structures and elastic network modes.
  21. (2005). Coarse-grained normal mode analysis in structural biology.
  22. (1966). Comparison of experimental binding data and theoretical models in proteins containing subunits.
  23. (2005). Comparison of tRNA motions in the free and ribosomal bound structures.
  24. (2001). Conformational change of proteins arising from normal mode calculations.
  25. (2002). Contact model for the prediction of NMR NH order parameters in globular proteins.
  26. (2006). Cooperative fluctuations point to the dimerization interface of p53 core domain.
  27. (2008). Designed protein-protein association.
  28. (1997). Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential.
  29. (2006). Dynamic coupling and allosteric behavior in a nonallosteric protein.
  30. (2007). Dynamic personalities of proteins.
  31. (2002). Dynamics of proteins in crystals: Comparison of experiment with simple models.
  32. (2004). ElNemo: a normal mode web server for protein movement analysis and the generation of templates for molecular replacement.
  33. (2009). Enzymatic Activity versus Structural Dynamics: The Case of Acetylcholinesterase Tetramer.
  34. (2002). Enzyme dynamics during catalysis.
  35. (2003). Evolutionarily conserved networks of residues mediate allosteric communication in proteins.
  36. (2002). Flexibility and packing in proteins.
  37. (2006). Functional modes of proteins are among the most robust.
  38. (2010). Global Dynamics of Proteins: Bridging Between Structure and Function.
  39. (2011). Grossfield A
  40. (2000). Harmonicity in slow protein dynamics.
  41. (2007). Inference of macromolecular assemblies from crystalline state.
  42. (2008). Influence of oligomerization on the dynamics of Gprotein coupled receptors as assessed by normal mode analysis.
  43. (2006). Interactions in native binding sites cause a large change in protein dynamics.
  44. (1998). Kidera A
  45. (2009). Kitao A
  46. (2004). Linkage between dynamics and catalysis in a thermophilicmesophilic enzyme pair.
  47. (2006). Markov propagation of allosteric effects in biomolecular systems: application to GroEL-GroES.
  48. (1989). Mechanisms of cooperativty and allosteric regulation in proteins.
  49. (1996). Motions in hemoglobin studied by normal mode analysis and energy minimization: Evidence for the existence of tertiary T-like, quaternary R-like intermediate structures.
  50. (2007). Network analysis of protein dynamics.
  51. (2002). Network of coupled promoting motions in enzyme catalysis.
  52. (2002). Normal mode analysis of macromolecular motions in a database framework: Developing mode concentration as a useful classifying statistic.
  53. (1965). On nature of allosteric transitions - A plausible model.
  54. (2010). On the Conservation of the Slow Conformational Dynamics within the Amino Acid Kinase Family: NAGK the Paradigm.
  55. (2001). On the quadratic reaction path evaluated in a reduced potential energy surface model and the problem to locate transition states.
  56. (1996). Principles of protein-protein interactions.
  57. (2005). Probing the local dynamics of nucleotide-binding pocket coupled to the global dynamics: Myosin versus kinesin.
  58. (2009). Protein Flexibility and Metal Coordination Changes in DHAP-Dependent Aldolases.
  59. (2005). Protein oligomerization: How and why.
  60. (1997). Protein-protein interactions: Interface structure, binding thermodynamics, and mutational analysis.
  61. (2000). Relationships between protein structure and dynamics from a database of NMR-derived backbone order parameters.
  62. (2008). Schenkel A
  63. (2007). Signal propagation in proteins and relation to equilibrium fluctuations.
  64. (2008). Structural and Functional Characterization of Escherichia coli UMP Kinase in Complex with Its Allosteric Regulator GTP.
  65. (2011). Structural and functional characterization of the Mycobacterium tuberculosis uridine monophosphate kinase: insights into the allosteric regulation.
  66. (2006). Structural bases of feed-back control of arginine biosynthesis, revealed by Oligomerization Effects
  67. (2005). Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state.
  68. (2002). Structure of acetylglutamate kinase, a key enzyme for arginine biosynthesis and a prototype for the amino acid kinase enzyme family, during catalysis.
  69. (2005). Structure of Escherichia coli UMP kinase differs from that of other nucleoside monophosphate kinases and sheds new light on enzyme regulation.
  70. (2010). Substrate Binding and Catalysis in Carbamate Kinase Ascertained by Crystallographic and Site-Directed Mutagenesis Studies: Movements and Significance of a Unique Globular Subdomain of This Key Enzyme for Fermentative ATP Production in Bacteria.
  71. (2006). Symmetry, form, and shape: Guiding principles for robustness in macromolecular machines.
  72. (2003). The course of phosphorus in the reaction of N-acetyl-L-glutamate kinase, determined from the structures of crystalline complexes, including a complex with an AlF4- transition state mimic.
  73. (2005). The crystal structure of Pyrococcus furiosus UMP kinase provides insight into catalysis and regulation in microbial pyrimidine nucleotide biosynthesis.
  74. (2007). The crystal structure of the complex of P-II and acetylglutamate kinase reveals how P-II controls the storage of nitrogen as arginine.
  75. (2009). The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding.
  76. (2007). Thorough validation of protein normal mode analysis: A comparative study with essential dynamics.
  77. (2010). Two Crystal Structures of Escherichia coli N-Acetyl-L-Glutamate Kinase Demonstrate the Cycling between Open and Closed Conformations.
  78. (1996). VMD: Visual molecular dynamics.