Modelling allosteric processes in E coli aspartate transcarbamylase

Biochimie
J CherfilsJ Janin

Abstract

The allosteric properties of aspartate transcarbamylase from E coli have been investigated by a combination of genetic, biochemical and structural studies. Based on the X-ray structures of the enzyme in T and R state established by Lipscomb et al, we have analyzed the interactions between the 12 polypeptide chains and have identified subunit interfaces that play a major part in the allosteric mechanism: the c1c4 interface between the 2 catalytic trimers, and one of 2 different interfaces between catalytic and regulatory chains, the c1r4 interface, which exists only in T state. We have modelled mutations affecting these interfaces: mutation pAR5 in the gene coding for r chains concerns the c1r4 interface, mutation Tyr----Phe 240 in the gene coding for c chains, the c1c4 interface. Both mutant proteins have reduced cooperativity and/or allosteric regulation by CTP and ATP. Molecular mechanic simulations lead to specific proposals for the structural origin of these effects, and some of the proposals can be checked by site-directed mutagenesis. Finally, we have modelled substrates bound at the active site of the T state, which binds aspartate less tightly than the R state and for which X-ray structures of bound substrate analogs we...Continue Reading

References

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Aug 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·S A Middleton, E R Kantrowitz
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May 1, 1965·Journal of Molecular Biology·J MONODJ P CHANGEUX

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Citations

Sep 30, 2006·Biochimica Et Biophysica Acta·J-M ZanottiM-C Bellissent-Funel

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