Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

PROTEIN FUNCTION
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Feedback inhibition is negative regulation: it prevents an enzyme from acting.
Enzymes can also be subject to positive regulation, in which a regulatory molecule
stimulates the enzyme’s activity rather than shutting the enzyme down. Positive
regulation occurs when a product in one branch of the metabolic network stimulates
the activity of an enzyme in another pathway. As one example, the accumulation
of ADP activates several enzymes involved in the oxidation of sugar molecules,
thereby stimulating the cell to convert more ADP to ATP.
Allosteric Enzymes Have Two or More Binding Sites That Interact
A striking feature of both positive and negative feedback regulation is that the regulatory
molecule often has a shape totally different from the shape of the substrate
of the enzyme. This is why the effect on a protein is termed allostery (from the
Greek words allos, meaning “other,” and stereos, meaning “solid” or “three-dimensional”).
As biologists learned more about feedback regulation, they recognized
that the enzymes involved must have at least two different binding sites on their
surface—an active site that recognizes the substrates, and a regulatory site that
recognizes a regulatory molecule. These two sites must somehow communicate
so that the catalytic events at the active site can be influenced by the binding of the
regulatory molecule at its separate site on the protein’s surface.
The interaction between separated sites on a protein molecule is now known
to depend on a conformational change in the protein: binding at one of the sites
causes a shift from one folded shape to a slightly different folded shape. During
feedback inhibition, for example, the binding of an inhibitor at one site on the
protein causes the protein to shift to a conformation that incapacitates its active
site located elsewhere in the protein.
It is thought that most protein molecules are allosteric. They can adopt two or
more slightly different conformations, and a shift from one to another caused by
the binding of a ligand can alter their activity. This is true not only for enzymes
but also for many other proteins, including receptors, structural proteins, and
motor proteins. In all instances of allosteric regulation, each conformation of the
protein has somewhat different surface contours, and the protein’s binding sites
for ligands are altered when the protein changes shape. Moreover, as we discuss
next, each ligand will stabilize the conformation that it binds to most strongly, and
thus—at high enough concentrations—will tend to “switch” the protein toward
the conformation that the ligand prefers.
Two Ligands Whose Binding Sites Are Coupled Must Reciprocally
Affect Each Other’s Binding
The effects of ligand binding on a protein follow from a fundamental chemical
principle known as linkage. Suppose, for example, that a protein that binds glucose
also binds another molecule, X, at a distant site on the protein’s surface. If
the binding site for X changes shape as part of the conformational change in the
protein induced by glucose binding, the binding sites for X and for glucose are
said to be coupled. Whenever two ligands prefer to bind to the same conformation
of an allosteric protein, it follows from basic thermodynamic principles that each
ligand must increase the affinity of the protein for the other. For example, if the
shift of a protein to a conformation that binds glucose best also causes the binding
site for X to fit X better, then the protein will bind glucose more tightly when X is
present than when X is absent. In other words, X will positively regulate the protein’s
binding of glucose (Figure 3–57).
Conversely, linkage operates in a negative way if two ligands prefer to bind
to different conformations of the same protein. In this case, the binding of the
first ligand discourages the binding of the second ligand. Thus, if a shape change
caused by glucose binding decreases the affinity of a protein for molecule X, the
binding of X must also decrease the protein’s affinity for glucose (Figure 3–58).
The linkage relationship is quantitatively reciprocal, so that, for example, if glucose
has a very large effect on the binding of X, X has a very large effect on the
binding of glucose.