Essential Cell Biology 5th edition

How Proteins Work
137
HOW PROTEINS WORK
For proteins, form and function are inextricably linked. Dictated by the
surface topography of a protein’s side chains, this union of structure,
chemistry, and activity gives proteins the extraordinary ability to orchestrate
the large number of dynamic processes that occur in cells. But the
fundamental question remains: How do proteins actually work? In this
section, we will see that the activity of proteins depends on their ability
to bind specifically to other molecules, allowing them to act as catalysts,
structural supports, tiny motors, and so on. The examples we review here
by no means exhaust the vast functional repertoire of proteins. However,
the specialized functions of the proteins you will encounter elsewhere in
this book are based on the same principles.
All Proteins Bind to Other Molecules
The biological properties of a protein molecule depend on its physical
interaction with other molecules. Antibodies attach to viruses or bacteria
as part of the body’s defenses; the enzyme hexokinase binds glucose and
ATP to catalyze a reaction between them; actin molecules bind to one
another to assemble into long filaments; and so on. Indeed, all proteins
stick, or bind, to other molecules in a specific manner. In some cases, this
binding is very tight; in others, it is weak and short-lived.
The binding of a protein to other biological molecules always shows great
specificity: each protein molecule can bind to just one or a few molecules
out of the many thousands of different molecules it encounters. Any substance
that is bound by a protein—whether it is an ion, a small organic
molecule, or a macromolecule—is referred to as a ligand for that protein
(from the Latin ligare, “to bind”).
The ability of a protein to bind selectively and with high affinity to a ligand
is due to the formation of a set of weak, noncovalent interactions—hydrogen
bonds, electrostatic attractions, and van der Waals attractions—plus
favorable hydrophobic forces (see Panel 2−3, pp. 70–71). Each individual
noncovalent interaction is weak, so that effective binding requires
many such bonds to be formed simultaneously. This is possible only if
the surface contours of the ligand molecule fit very closely to the protein,
matching it like a hand in a glove (Figure 4−31).
When molecules have poorly matching surfaces, few noncovalent interactions
occur, and the two molecules dissociate as rapidly as they come
together. This is what prevents incorrect and unwanted associations
from forming between mismatched molecules. At the other extreme,
when many noncovalent interactions are formed, the association will
persist (see Movie 2.4). Strong binding between molecules occurs in cells
whenever a biological function requires that the molecules remain tightly
associated for a long time—for example, when a group of macromolecules
come together to form a functional subcellular structure such as
a ribosome.
The region of a protein that associates with a ligand, known as its binding
site, usually consists of a cavity in the protein surface formed by
a particular arrangement of amino acid side chains. These side chains
can belong to amino acids that are widely separated on the linear polypeptide
chain, but are brought together when the protein folds (Figure
4−32). Other regions on the surface often provide binding sites for different
ligands that regulate the protein’s activity, as we discuss later. Still
other parts of the protein may be required to attract or attach the protein
to a particular location in the cell—for example, the hydrophobic α helix
of a membrane-spanning protein allows it to be inserted into the lipid
bilayer of a cell membrane (see Figure 4−15 and discussed in Chapter 11).
(A)
(B)
QUESTION 4–4
Hair is composed largely of fibers
of the protein keratin. Individual
keratin fibers are covalently crosslinked
to one another by many
disulfide (S–S) bonds. If curly hair is
treated with mild reducing agents
that break a few of the cross-links,
pulled straight, and then oxidized
again, it remains straight. Draw a
diagram that illustrates the three
different stages of this chemical and
mechanical process at the level of
the keratin filaments, focusing on
the disulfide bonds. What do you
think would happen if hair were
treated with strong reducing agents
that break all the disulfide bonds?
noncovalent bonds
ligand
protein
Figure 4−31 The binding of a protein to
another molecule is highly selective.
Many weak interactions are needed to
enable a protein to bind tightly to a second
molecule (a ECB5 ligand). 04.31 The ligand must
therefore fit precisely into the protein’s
binding site, so that a large number of
noncovalent interactions can be formed
between the protein and the ligand.
(A) Schematic drawing showing the binding
of a hypothetical protein and ligand;
(B) space-filling model of the ligand–protein
interaction shown in Figure 4−32.