Biology Reference
In-Depth Information
11.4.2 Integrins
Integrins are heterodimeric transmembrane molecules, held together by
non-covalent interactions and constitutively expressed in a wide variety
of cells. Integrins mediate cell adhesion by binding to components of the
extracellular matrix or to another cell by binding to members of the IgSF. The
N-terminal region of all
A
subunits is made up of seven repeats that form a
B
“
-propeller” structure. In half of the integrins, a 200-residue, Rossmann fold
“I-domain” is inserted between the
-propeller repeats 2 and 3. A divalent
cation coordination site, designated the metal ion-dependent adhesion site
in the I-domain, binds negatively charged residues in ligands. A similar “
B
B
I-
B
domain” structure is found in the N-terminal of the
subunit, which is directly
involved in ligand binding in integrins that lack I-domains in the
A
A
B
and
chain are important in regulating integrins' global conformation, afinity and
the bidirectional signals crossing through the cell membrane.
94
Afinity regulation is an important functional feature of all integrins. The
strength of the integrin-ligand bond is drastically increased when the integrin
molecule is activated through intracellular signals. Although the detailed
molecular mechanism of afinity regulation is still obscure, it is shown that
integrin activation is associated with a dramatic change of its overall global
conformation. One of the most popular hypotheses is the separation of the
two “legs” of the integrin; this separation results from a binding of activation
adaptor molecules into the cytoplasmic tails during inside-out signaling.
94
Because of its unique capability of characterizing in situ the strength of
single molecular interactions, AFM became an ideal tool to probe the different
activation states of integrins. Zhang
et al.
and Li
et al.
were able to observe
A
B
A
B
the activation process of integrin
1
, respectively. It has been
found that resting integrins form short-lived receptor-ligand complexes of
a fraction of seconds, whereas after activation, their lifetime increases about
100 folds.
5,33
Moreover, Kong
2
and
L
5
1
also
formed catch bonds when interacting with ibronectin,
22
indicating a more
general mechanism for protein conformation of higher afinity induced
by force
et al.
proposed recently that integrin
A
B
5
.
It is noteworthy that a number of studies used AFM tips functionalized
with integrin expressing cells.
39,95,96
This approach ensures that the
heterodimeric integrin is under conditions close to the native environment,
which has allowed researchers to monitor adhesion following cell activation
in a whole cell level.
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