Page 177 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

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Encyclopedia of Physical Science and Technology EN013D-616 July 27, 2001 12:5

Protein Structure 217

protein stability, the overall stability of multimeric assem- the protein subunits that serve to alter the position of the
bliesisproportionaltothehydrophobicsurfaceareaburied polypeptide chains or cofactors within the regions respon-
within the interface. sible for ligand binding or catalytic activity. Allosteric
A large number of enzymes exist as symmetric macro- effectors serve to either inhibit or enhance these confor-
molecular assemblies where they commonly exhibit C and mational changes. Thus in all cases the active site residues
D point group symmetries and contain two-, three-, four-, are influenced either directly or indirectly by the protein–
and six-fold axes of symmetry. In the simplest cases this protein interactions between subunits. Typically a rotation
◦
feature provides additional thermodynamic stability for of subunits of 5–15 is sufficient to accomplish allosteric
a protein that would otherwise be rather small. In more control.
complex arrangements the protein–protein interfaces form
the active site such that the oligomerization is required
B. Viruses
for function. Finally, in the most highly evolved enzymes
there is communication between the active sites that re- Viruses represent particularly evolved forms of macro-
side on symmetrically related subunits. This provides the molecular assemblies. Mature virions are encoded by a
foundation for enzyme regulation as observed in most al- protective coat that is formed in part by virally encoded
losteric enzymes. proteins. Viruses come in many shapes and sizes, but they
all share the property of using multiple copies of coat
proteins to protect their genomic material. In many cases
A. Allosteric Enzymes
the proteins assemble to form a symmetric shell, where
The simplest model for allosteric control was set forward the symmetries are either helical as found in tobacco mo-
by Monod, Changeux, and Jacob in 1963 and provided saic virus or icosahedral as seen in the spherical viruses.
the basis for understanding feedback inhibition and co- The use of multiple copies of a protein to form a vi-
operative binding of ligands by proteins. In their model ral coat is enormously efficient from a genomic point of
it was assumed that an allosteric enzyme (or protein) ex- view; however, it introduces several interesting structural
ists in equilibrium between two symmetric states; inactive problems.
and active (T and R states). The transition between these Allsimplesphericalvirusesexhibiticosahedralsymme-
states was assumed to be concerted, that is the symme- try. This implies that the surface contains 60 equivalent po-
try of the macromolecular assembly is conserved. Fur- sitions or that the shell is built from 60 equivalent protein
thermore the active state has a greater affinity for sub- subunits. Although this is observed for a few very small
strate than the inactive state. From these considerations virus particles, most contain many more than 60 subunits.
the activity of the enzyme depends on the position of the For example the viral shell of most small plant viruses con-
equilibrium between the inactive and active states. Thus tains 180 identical protein subunits. This poses a problem
increasing the substrate concentration drives the equilib- of how to arrange 180 subunits on the surface of an icosa-
rium to the active form and gives rise to a sigmoidal re- hedral shell since the subunits cannot experience sym-
lationship between the initial velocity of the reaction and metrically equivalent environments. Fifty years ago it was
the substrate concentration. As importantly the position proposed by Caspar and Klug that viral subunits would be
of the equilibrium can be altered by allosteric effectors arranged on a hexagonal surface lattice with quasiequiva-
that preferentially bind to either the inactive or active lent symmetry where the contacts between subunits would
state. This is the basis of feedback inhibition whereby be organized to minimize their differences in assembly.
the product of a biosynthetic pathway inhibits the en- That is, if a virus contains 180 subunits on its surface,
zyme that catalyzes the first committed step. This sim- these would be grouped into three sets of 60 subunits
ple model explains many of the properties of allosteric where each group would experience similar interactions
enzymes; however, a more complex model based on se- compared to the other groups. At first sight this hypoth-
quential binding of substrates to yield multiple conforma- esis accounts for the structure of simple viruses where it
tion states is required to explain the finer details of many has been shown that most of the interactions between the
enzymes. protomers on the surface are essentially identical; how-
The structural basis of allostery has been well devel- ever, closer examination of the virus structures that have
oped through the study of enzymes such as aspartate tran- been determined reveals that in all cases the groups of
scarbamoylase and phosphofructokinase. In all enzymes protomers behave as though they are different proteins by
studied thus far several common themes have evolved. utilizing their domains in different ways to accommodate
First the overall symmetry of the inactive and active states their structurally unique environments (Fig. 18). Thus, it
appear to be conserved. Second the transition between would appear that the main requirement for a virus coat
these states involves a change in the relationship between protein is to have a shape and conformational flexibility to