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First Class Lecture notes Dynamic Cell Module
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Integrins lecture notes
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LEARNING WHEN TO ATTACH AND LET GO WITHINTEGRINS…
What is the role of fibronectin in the ECM?
Fibronectin and other multidomain glycoproteins organise the ECM
and cell attachment
Relatively minor components within the ECM
(in terms of amount). Many are glycoproteins
(not the same as proteoglycans) – have
covalent links to carbohydrates (sugars).
Fibronectins are large proteins with
multidomain structures, containing multiple
type I-III repeat domains (FN1, FN2 and FN3
which is particularly frequent in fibronectins)
These domains make up most of the
fibronectin and facilitate binding to integrins,
collagen fibres, fibrin and heparin.
FN is encoded by a single gene but contains 50
exons (>50kb), so there are more than 20
splice variants with different functions due to
domain architecture.
Fibronectin helps cells attach to the matrix
Large glycoprotein- all forms encoded by a
single gene: can be soluble (dimer) or insoluble
(forms higher order polymers)
Dimer, usually a heterodimer of different
fibronectin splice variants – two subunits joined
by disulphide bonds
Different domains interact with different
targets, which are easily identified by deletion
construct experiments. Integrin binding domain
(RGD peptide sequence in FN3 repeats) is very
important in interaction with the ECM and
governing formation into insoluble fibrillary form, which is an important part of the clotting
response. This process can be disrupted if the system is attacked by anticoagulants, e.g.
some viper snake venoms, which mimic the RGD peptide sequence and prevents
fibronectins binding to integrins, blocking clot formation.
Fibronectin can unfold to form fibrils in response to tension
Similar to fibril-forming collagens, which
have pro-peptide domains on the C and N
, terminus of the protein which are cleaved outside the cell, triggering spontaneous assembly
into fibrils and fibres. If this occurred inside the cell, the cell would burst.
Fibronectin is also capable of forming insoluble fibronectin fibrils in which dimers are linked
to form part of the ECM. This is a reversible process which only occurs on the surface of
cells, and only where those cells possess appropriate fibronectin-binding proteins (integrins).
Integrins regulate fibril formation because in the soluble dimer form, they are folded up –
fibronectin forms dimers using cysteine bridges at the C terminus, and this soluble form of
fibronectin does not spontaneously assemble into fibres (default state circulating in the
blood and other body fluids).
Integrins provide a linkage from the fibronectin outside the cell to the actin cytoskeleton
inside it, and this linkage transmits tension to the fibronectin molecules and stretches them,
exposing a cryptic binding site. This allows them to bind directly to one another and recruit
additional fibronectin molecules to forma fibril.
Why is this important?
Allows binding of fibronectin molecules to one another
Promotes fibril formation where there is mechanical need for them and not in inappropriate
locations such as the bloodstream
Fibronectin can organise into fibrils at the cell surface
Demonstrated by the deposition of fibronectins in the leading edge of a mouse
fibroblast. Mouse fibroblast attached to a substrate which includes fibronectin as one of
the adhesion molecules – cells attach and form stress fibres/contractile actin filaments
shown in red. Fibronectin fibrils (green) are clearly concentrated in the vicinity of these
stress fibres, because the fibronectin fibrils require other proteins including integrins in
order to assemble. At the ends of actin filaments there is an adhesion complex, at the centre
of which are integrin receptors which bind to the ECM, including fibronectin. This exerts
tension on fibronectin, stretching out the molecules into fibrils. Hence, it appears that
fibronectin fibrils are continuous with the cytoskeleton.
What are integrins and what is the structure
of the integrin molecule?
Epithelial cells are anchored to the ECM by α6β4 integrin in hemidesmosomes
Integrins are the principle receptors for ECM
components. The interaction between intermediate
cytoskeletal filaments (keratin filaments) and the ECM
is mediated through integrins in a hemidesmosome
structure. In hemidesmosomes, a single integrin binds
laminin and collagen IV in the basal lamina (so this
interaction only occurs in epithelial cells).
Recurrent theme of transmembrane receptor,
cytoplasmic adaptor protein complex that mediate
interaction between receptor and cytoskeleton, and
outside receptors interact with ECM (basal lamina formed of collagen 4, laminin, recognized
by cells).
Integrin has 2 subunits (alpha and beta), and in this case the subunits involved are alpha 6
and beta 4. Different combinations of subunits give different types of integrin which are
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