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

TRANSPORTERS AND ACTIVE MEMBRANE TRANSPORT
603
EXTRACELLULAR SPACE
glucose Na +
plasma membrane
Na +
electrochemical
gradient
glucose
concentration
gradient
CYTOSOL
occludedempty
outwardopen
occludedoccupied
inwardopen
occludedempty
Figure 11–9 Mechanism of glucose transport fueled by a Na + gradient. As in the model shown in Figure 11–5,
the transporter alternates between inward-open and outward-open states via an occluded intermediate state. Binding of
Na + and glucose is cooperative—that is, the binding of either solute increases the protein’s affinity for the other. Since the
Na + concentration is much higher in the extracellular space than in the cytosol, glucose is more likely to bind to the transporter
in the outward-facing state. The transition to the occluded state occurs only when both Na + and glucose are bound; their
precise interactions in the solute-binding sites slightly stabilize the occluded state and thereby make this transition energetically
favorable. Stochastic fluctuations caused by thermal energy drive the transporter randomly into the inward-open or outwardopen
conformation. If it opens outwardly, nothing is achieved, and the process starts all over. However, whenever it opens
inwardly, Na + dissociates quickly in the low-Na + -concentration environment of the cytosol. Glucose dissociation is likewise
enhanced when Na + is lost, because of cooperativity in binding of the two solutes. The overall result is the net transport of
both Na + MBoC6 m11.09/11.09
and glucose into the cell. Because the occluded state is not formed when only one of the solutes is bound, the
transporter switches conformation only when it is fully occupied or fully empty, thereby assuring strict coupling of the transport
of Na + and glucose.
into the cell (Figure 11–9). Neurotransmitters (released by nerve cells to signal at
synapses—as we discuss later) are taken up again by Na + symporters after their
release. These neurotransmitter transporters are important drug targets: stimulants,
such as cocaine and antidepressants, inhibit them and thereby prolong signaling
by the neurotransmitters, which are not cleared efficiently.
Despite their great variety, transporters share structural features that can
explain how they function and how they evolved. Transporters are typically
built from bundles of 10 or more α helices that span the membrane. Solute- and
ion-binding sites are located midway through the membrane, where some helices
are broken or distorted and amino acid side chains and polypeptide backbone
atoms form ion- and solute-binding sites. In the inward-open and outward-open
conformations, these binding sites are accessible by passageways from one side of
the membrane but not the other. In switching between the two conformations, the
transporter protein transiently adopts an occluded conformation, in which both
passageways are closed; this prevents the driving ion and the transported solute
from crossing the membrane unaccompanied, which would deplete the cell’s
energy store to no purpose. Because only transporters with both types of binding
sites appropriately filled change their conformation, tight coupling between ion
and solute transport is assured.
Like enzymes, transporters can work in the reverse direction if ion and solute
gradients are appropriately adjusted experimentally. This chemical symmetry is
mirrored in their physical structure. Crystallographic analyses have revealed that
transporters are built from inverted repeats: the packing of the transmembrane α
helices in one half of the helix bundle is structurally similar to the packing in the
other half, but the two halves are inverted in the membrane relative to each other.
Transporters are therefore said to be pseudosymmetric, and the passageways
that open and close on either side of the membrane have closely similar geometries,
allowing alternating access to the ion- and solute-binding sites in the center
(Figure 11–10). It is thought that the two halves evolved by gene duplication of a
smaller ancestor protein.