Abstract
Coupling of structural flexibility and biological function is an essential feature of proteins. The role of relative domain movements in enzyme function has been evidenced in many cases. However, the way of communication between protein domains and its manifestation in their movements as well as in the biological function are rarely delineated. In this review we summarize comprehensive studies with a typical hinge-bending two-domain enzyme, 3-phosphoglycerate kinase. A possible mechanism is proposed by which the two substrates that bind to different domains trigger the operation of the molecular hinges, located in the interdomain region. Various crystal structures of the enzyme have been determined with different relative domain positions, suggesting that domain closure brings the two substrates together for the catalysis. Substrate-caused conformational changes in the binary and the ternary complexes have been tested with the solubilized enzyme using physical methods, such as differential scanning calorimetry, small angle X-ray scattering and infrared spectroscopy. The results indicated the existence of strong cooperativity between the two domains and that the presence of both substrates is necessary for the domain closure. Comparison of the atomic contacts in the structures has led to selection of conserved side-chains, which may be involved in the domain movement. On this basis a hypothesis was put forward about the molecular mechanism of interdomain co-operation. Enzyme kinetic, ligand binding and small angle X-ray scattering studies with various site-directed mutants have confirmed this hypothesis. Namely, a special H-bonding network (a double molecular switch) seems to be responsible for operation of the main molecular hinge at the β-strand L under the concerted action of both substrates.
Keywords: Conformational flexibility, domain motion, substrate binding, enzyme function, 3-phosphoglycerate kinase
Current Protein & Peptide Science
Title: Insight into the Mechanism of Domain Movements and their Role in Enzyme Function: Example of 3-Phosphoglycerate Kinase
Volume: 11 Issue: 2
Author(s): M. Vas, A. Varga and E. Graczer
Affiliation:
Keywords: Conformational flexibility, domain motion, substrate binding, enzyme function, 3-phosphoglycerate kinase
Abstract: Coupling of structural flexibility and biological function is an essential feature of proteins. The role of relative domain movements in enzyme function has been evidenced in many cases. However, the way of communication between protein domains and its manifestation in their movements as well as in the biological function are rarely delineated. In this review we summarize comprehensive studies with a typical hinge-bending two-domain enzyme, 3-phosphoglycerate kinase. A possible mechanism is proposed by which the two substrates that bind to different domains trigger the operation of the molecular hinges, located in the interdomain region. Various crystal structures of the enzyme have been determined with different relative domain positions, suggesting that domain closure brings the two substrates together for the catalysis. Substrate-caused conformational changes in the binary and the ternary complexes have been tested with the solubilized enzyme using physical methods, such as differential scanning calorimetry, small angle X-ray scattering and infrared spectroscopy. The results indicated the existence of strong cooperativity between the two domains and that the presence of both substrates is necessary for the domain closure. Comparison of the atomic contacts in the structures has led to selection of conserved side-chains, which may be involved in the domain movement. On this basis a hypothesis was put forward about the molecular mechanism of interdomain co-operation. Enzyme kinetic, ligand binding and small angle X-ray scattering studies with various site-directed mutants have confirmed this hypothesis. Namely, a special H-bonding network (a double molecular switch) seems to be responsible for operation of the main molecular hinge at the β-strand L under the concerted action of both substrates.
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Cite this article as:
Vas M., Varga A. and Graczer E., Insight into the Mechanism of Domain Movements and their Role in Enzyme Function: Example of 3-Phosphoglycerate Kinase, Current Protein & Peptide Science 2010; 11 (2) . https://dx.doi.org/10.2174/138920310790848403
DOI https://dx.doi.org/10.2174/138920310790848403 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
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