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

CELL–MatrIX JUNCTIONS
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receptor on many types of cells. Mutant mice that cannot make any β 1 integrins
die early in embryonic development. Mice that are only unable to make the α 7
subunit (the partner for β 1 in muscle) survive but develop muscular dystrophy (as
do mice that cannot make the laminin ligand for the α 7 β 1 integrin).
The β 2 subunit forms dimers with at least four types of α subunit and is
expressed exclusively on the surface of white blood cells, where it has an essential
role in enabling these cells to fight infection. The β 2 integrins mainly mediate cell–
cell rather than cell–matrix interactions, binding to specific ligands on another
cell, such as an endothelial cell. The ligands are members of the Ig superfamily of
cell–cell adhesion molecules. We have already described an example earlier in the
chapter: an integrin of this class (α L β 2 , also known as LFA1) on white blood cells
enables them to attach firmly to the Ig family protein ICAM1 on vascular endothelial
cells at sites of infection (see Figure 19–28B). People with the genetic disease
called leukocyte adhesion deficiency fail to synthesize functional β 2 subunits. As
a consequence, their white blood cells lack the entire family of β 2 receptors, and
they suffer repeated bacterial infections.
The β 3 integrins are found on blood platelets (as well as various other cells),
and they bind several matrix proteins, including the blood clotting factor fibrinogen.
Platelets have to interact with fibrinogen to mediate normal blood clotting,
and humans with Glanzmann’s disease, who are genetically deficient in β 3 integrins,
suffer from defective clotting and bleed excessively.
Integrins Can Switch Between an Active and an Inactive
Conformation
A cell crawling through a tissue—a fibroblast or a macrophage, for example, or an
epithelial cell migrating along a basal lamina—has to be able both to make and to
break attachments to the matrix, and to do so rapidly if it is to travel quickly. Similarly,
a circulating white blood cell has to be able to switch on or off its tendency to
bind to endothelial cells in order to crawl out of a blood vessel at a site of inflammation.
Furthermore, if force is to be applied where it is needed, the making and
breaking of the extracellular attachments in all these cases has to be coupled to
the prompt assembly and disassembly of cytoskeletal attachments inside the cell.
The integrin molecules that span the membrane and mediate the attachments
cannot simply be passive, rigid objects with sticky patches at their two ends. They
must be able to switch between an active state, where they readily form attachments,
and an inactive state, where they do not.
Structural studies, using a combination of electron microscopy and x-ray crystallography,
suggest that integrins exist in multiple structural conformations that
reflect different states of activity (Figure 19–57). In the inactive state, the external
segments of the integrin dimer are folded together into a compact structure that
cannot bind matrix proteins. In this state, the cytoplasmic tails of the dimer are
strong
ligand binding
INACTIVE
INTEGRIN
ACTIVE
INTEGRIN
β
α
5 nm
strong
adaptor-protein
binding
Figure 19–57 Integrins exist in two
major activity states. Inactive (folded)
and active (extended) structures of an
integrin molecule, based on data from x-ray
crystallography and other methods.