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The morpheein model of allostery: evaluating proteins as potential morpheeins.

ABSTRACT: An equilibrium mixture of alternate quaternary structure assemblies can form a basis for allostery. The morpheein model of allostery is a concerted dissociative model that describes an equilibrium of alternate quaternary structure assemblies whose architectures are dictated by alternate conformations in the dissociated state. Kinetic and biophysical anomalies that suggest that the morpheein model of allostery applies for a given protein of interest are briefly described. Two methods are presented for evaluating proteins as potential morpheeins. One is a subunit interchange method that uses chromatography, dialysis, and mass spectroscopy to monitor changes in multimer composition. The other is a two-dimensional native gel electrophoresis method to monitor ligand-induced changes in an equilibrium of alternate multimeric assemblies.

SUBMITTER: Jaffe EK

PROVIDER: S-EPMC3256758 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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The morpheein model of allostery: evaluating proteins as potential morpheeins.

Jaffe Eileen K EK Lawrence Sarah H SH

Methods in molecular biology (Clifton, N.J.) 20120101

An equilibrium mixture of alternate quaternary structure assemblies can form a basis for allostery. The morpheein model of allostery is a concerted dissociative model that describes an equilibrium of alternate quaternary structure assemblies whose architectures are dictated by alternate conformations in the dissociated state. Kinetic and biophysical anomalies that suggest that the morpheein model of allostery applies for a given protein of interest are briefly described. Two methods are presente ...[more]

PMID: 22052493

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Project description:Aspartate carbamoyltransferase (ATCase) is a large dodecameric enzyme with six active sites that exhibits allostery: its catalytic rate is modulated by the binding of various substrates at distal points from the active sites. A recently developed method, bond-to-bond propensity analysis, has proven capable of predicting allosteric sites in a wide range of proteins using an energy-weighted atomistic graph obtained from the protein structure and given knowledge only of the location of the active site. Bond-to-bond propensity establishes if energy fluctuations at given bonds have significant effects on any other bond in the protein, by considering their propagation through the protein graph. In this work, we use bond-to-bond propensity analysis to study different aspects of ATCase activity using three different protein structures and sources of fluctuations. First, we predict key residues and bonds involved in the transition between inactive (T) and active (R) states of ATCase by analysing allosteric substrate binding as a source of energy perturbations in the protein graph. Our computational results also indicate that the effect of multiple allosteric binding is non linear: a switching effect is observed after a particular number and arrangement of substrates is bound suggesting a form of long range communication between the distantly arranged allosteric sites. Second, cooperativity is explored by considering a bisubstrate analogue as the source of energy fluctuations at the active site, also leading to the identification of highly significant residues to the T???R transition that enhance cooperativity across active sites. Finally, the inactive (T) structure is shown to exhibit a strong, non linear communication between the allosteric sites and the interface between catalytic subunits, rather than the active site. Bond-to-bond propensity thus offers an alternative route to explain allosteric and cooperative effects in terms of detailed atomistic changes to individual bonds within the protein, rather than through phenomenological, global thermodynamic arguments.

Dataset Information

The morpheein model of allostery: evaluating proteins as potential morpheeins.

Publications

The morpheein model of allostery: evaluating proteins as potential morpheeins.

Similar Datasets

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