BCH 403 Material

E.
Allosteric Proteins
The cooperativity of oxygen binding to hemoglobin is a classic model for the behavior
of many other multisubunit proteins (including certain enzymes)
Section 7-2. Hemoglobin179
T-state
that bind small molecules. In some cases, binding of a ligand to one site in-cresses the aftinity of
otherbinding sites on the same protein (as in O binding to hemoglobin). In other cases, a ligand decreases
the affinity of other binding sites (as when BPG binding decreases the O,affinity of he-moglobin). All these
effeets are the result of allosteric interactions (Greck:allos,other +stereos, solid or space). Allosteric
effects, in wehich the bind-ing of a ligand at one site affects the binding of another ligand at another site,
generally require interactions among subunits of oligomeric proteins.The T →R transition in hemoglobin
subunits explains the difference in the ogen affinities of oxy- and deoxyhemoglobin. Other protens exhibit
sim-ilar conformational shifts, although the molecular mechanisms that under-lie these phenomena are
not completely understood.
Iwo models that account for cooperative ligand binding have received the most attention. One of
them,the symmetry model of allosterism, for-mulated in 1965 by Jacques Monod, Jeffries Wyman,and
Jean-Pierre Changeux, is defined by the following rules:
1.An allosteric protein is an oligomer of symmetrically related subunits (although the a and β subunits of hemoglobin are only pseudosym-
metrically related).
2. Each subunit can exist in two conformational states,designated R and T: these states are in equilibrium.
3. The ligand can bind to a subunit in either conformation. Only the con-formational change alters the affinity for the ligand.
4. The molecular symmetry of the protein is conserved during the con-formational S S
change. The subunits must therefore change conforma-tion in a concerted manner; in
other words, there are no oligomers that simultancously contain R- and T-state
S S
subunits. Figure 7-19. The symmetry model of alloster-ism. Squares and
The symmetry model is diagrammed for a tetrameric binding protein in Fig. 7-19. If a ligand binds circles represent T-and R-state subunts, respectively, of a
tetrameric protein The T and R states are in equilibrium
more tightly to the R state than to the T state.ligand binding will promote the T → R shift, thereby
regardless of the number of hgands(represented by S) that
increasing the affin-ity of the unliganded subunits for the ligand.
have bound to the protein All the subunits must be in either
One major objection to the symmetry model is that it is difficult to be-lieve that oligomeric
the T or the R form,the model does not allow combinations of
symmetry is perlectly preserved in all proteins. that is.that the T → R shift occurs simultaneously in T-and R-state subunits in the same protein
all subunits regardless of the number of ligands bound. In addition, the symmetry model can
account only for positive cooperativity, although some proteins exhibit negative cooperativity.
An alternative to the symmetry model is the sequential model of al-losterism. proposed by
Daniel Koshland. According to this model. ligand binding induces a conformational change in the
subunit to which it hinds.and cooperative interactions arise through the inlluence of those confor-
mational changes on neighboring subunits. The conformational changes oc-cur sequentially as more
ligand-binding sites are occupied (Fig.7-20).The
S S
Figure 7-20. The sequential model of allosterism. Ligand binding progressively Induces conformational changes in the subunits, with the greatest changes occurning in those subunits
that have bound ligand. The symmetry of the oligomeric protein is not preserved in this process as it is in the symmetry model.
ligand-binding affinity of a subunit varies with its conformation and may be higher or lower than that of
the subunits in the ligand-free protein.Thus.proteins that follow the sequential model of allosterism may
be positively or negatively cooperative.
If the mechanical coupling between subunits in the sequential model is particularl strong, the
conformational changes occur simultancously and the oligomer retains its symmetry,as in the
symmetry model. Thus,the sym-metry model of allosterism may be considered to be an extreme
case of the more general sequential model.
Oxygen binding to hemoglobin exhibits features of both models. The quaternary T → R
conformational change is concerted. as the symmetry model requires. Yet ligand binding to the T
state does cause small tertiary structural changes. as the sequential model predicts. These minor
confor-mational shifts are undoubtedly responsible for the buildup of strain that eventualy triggers
the T →R transition. It therefore appears that the com-plexity of ligand-protein interactions in
hemoglobin and other proteins allows binding processes to be fine-tuned to the needs of the
organism un-der changing internal and external conditions. We shall revisit allosteric ef-fects when
we discuss enzymes in Chapter 12.

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