J. Anat. (1998) 193, pp. 1–21, with 8 figuresPrinted in the United Kingdom
The role of laminins in basement membrane function
MONIQUE AUMAILLEY AND NEIL SMYTH
Institut fu ? r Biochemie II, Medical Faculty, Cologne, Germany
(Accepted 6 April 1998)
Laminins are a family of multifunctional macromolecules, ubiquitous in basement membranes, and represent
the most abundant structural noncollagenous glycoproteins of these highly specialised extracellular matrices.
Their discovery started with the difficult task of isolating molecules produced by cultivated cells or extracted
from tissues. The development of molecular biology techniques has facilitated and accelerated the
identification and the characterisation of new laminin variants making it feasible to identify full-length
polypeptides which have not been purified. Further, genetically engineered laminin fragments can be
generated for studies of their structure-function relationship, permitting the demonstration that laminins are
involved in multiple interactions with themselves, with other components of the basal lamina, and with cells.
It endows laminins with a central role in the formation, the architecture, and the stability of basement
membranes. In addition, laminins may both separate and connect different tissues, i.e. the parenchymal and
the interstitial connective tissues. Laminins also provide adjacent cells with a mechanical scaffold and
biological information either directly by interacting with cell surface components, or indirectly by trapping
growth factors. In doing so they trigger and control cellular functions. Recently, the structural and
biological diversity of the laminins has started to be elucidated by gene targeting and by the identification of
laminin defects in acquired or inherited human diseases. The consequent phenotypes highlight the pivotal
role of laminins in determining heterogeneity in basement membrane functions.
Key words: Extracellular matrix; congenital muscular dystrophy; epidermolysis bullosa.
Purification and characterisation of a laminin mol-
ecule began in 1979 with the observation that the
stroma of a tumour transplantable to the mouse, the
Engelbreth–Holm–Swarm (EHS) tumour, contained
large amounts of basement membrane-like material.
Besides collagen IV, the most abundant collagen of
the basal lamina, a noncollagenous component, was
present in substantial quantities. It was purified,
identified as a large glycoprotein, and named laminin
(Timpl et al. 1979). For several years, this was the only
known laminin, but it was in fact the first member of
a family of molecules which has now grown to more
than 10 and which is the focus of extensive study
recently reviewed in ‘The Laminins’ (Ekblom &
Laminins are heterotrimers constituted by the
Correspondence to Dr Monique Aumailley, Institut fu ? r Biochemie II, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany. Tel:
?49 221 478 6991; fax: ?49 221 478 6977; e-mail: Aumailley?uni-koeln.de
association of 3 different gene products, the α, β and
γ chains (Burgeson et al. 1994). To date, 5 α (α1–5), 3
β (β1–3), and 2 γ (γ1,γ2) chains have been identified
and the search for novel chains is now intensive. The
sequences deduced from cDNA clones (Fig. 1) show
that laminin chains are formed by common and
specific modules so that the molecules are chimeras of
homologous structural domains, some of them
laminin-specific and others being shared with non-
laminin molecules (Engel, 1991).
Similarities in the carboxy-terminal regions
For all these chains, the deduced sequences show the
presence of a ?600 residue-carboxy terminal region,
domains I and II, characterised by repeated heptad
Fig. 1. Schematic representation of the domain organisation of different laminin chains. The characteristic LE motifs (ellipses), cysteine-poor
domains (circles), coil-coiled regions (lines) and the G domain (shaded circles) are shown.
peptides typical of polypeptides that fold into coil-
coiled dimers or trimers. In the β chains the heptad
repetition is interrupted by a stretch of amino acids at
the border between domains I and II. The α chains
contain an additional domain at the carboxy-terminus
which is conserved between the chains and which can
be subdivided into 5 sequence repeats, the G1 to G5
subdomains (Fig. 1).
Variations in the amino-terminal regions
The amino-terminal sequences are constituted by 2
domain types. One, a cysteine-rich 60 amino acid
domain, occurs repeatedly and is shared by many
other polypeptides. These LE motifs, according to the
nomenclature adopted by the SWISS-PROT data
Bank, have homology to the epidermal growth factor
(EGF), except for the presence of 6 cysteine residues
in EGF versus 8 residues in the laminin motif. These
motifs are arranged in rows and form domains III and
V, which are either interspaced by or contain inserted
laminin-specific cysteine-poor regions, the domains
IV. The most N-terminal portion, domain VI is again
a cysteine rare area. The rows of successive LE motifs
form rods with a certain degree of flexibility and may
representspacers between biologically active domains.
The presence, location, and numbers of domains IV
and VI, as well as the number of LE motifs vary with
the laminin chains (Fig. 1). The classical or full-length
α1, α2 and α5 chains, and presumably the α3B variant
(Miner et al. 1997), contain 3 cysteine poor stretches
of residues: the amino-terminal domain VI, and 2
domains IV (IVa and IVb), each inserted as separate
loops between 2 cysteine residues of a LE motif, so
that the row of LE motifs (17 for α1 and α2, 21 for α5)
is probably not interrupted. By contrast, the amino-
terminal portion of the α3A and α4 chains is very
short and contains only 2–3 LE motifs, a terminal
rudimentary domain IV, and no domain VI. The β1
and β2 chains contain 13 LE modules, 1 domain IV
intercalated between 2 LE motifs, so that the LE row
is probably interrupted, and an amino-terminal
domain VI. The γ1 chain is a little shorter, having 11
LE motifs, 1 domain IV inserted within an LE motif,
and a domain VI. The β3 and γ2 chains are the most
divergent from the others, the β3 chain having 6 LE
motifs, no domain IV and a terminal domain VI,
while the γ2 chain, with 8 LE motifs, has 1 domain IV
and no domain VI.
The laminin 1 model
Laminin 1, the first member of the family isolated
from the EHS tumour, and frequently referred to as
EHS laminin, is constituted by the α1 (?400 kDa),
β1 and γ1 (each ?200 kDa) chains. Electron mi-
croscopy observation of rotary-shadowed molecules
indicated that the 3 chains are associated to form a
cross with 3 short arms, 1 with a length of 48 nm and
2 of 34 nm, with 3 and 2 globular domains re-
spectively, and a long arm of 77 nm terminated by a
larger globular domain.
M. Aumailley and N. Smyth
Fig. 2. The laminin family: representation of laminin heterotrimers. The α?β?γ associations identified to-date are listed and the variable
domains refer to Fig. 1.
A proposed structural model is based on the
correlation of sequence data with protein chemistry
and electron microscopy observation of laminin 1 and
its purified proteolytic fragments. The short arms are
separately formed by the amino-terminal region of the
chains with globular folding of the domains IV and
VI, and rod alignment of the LE motifs (domains III
and V). The long arm results from folding together the
carboxy-terminal domains I and II of the α1, β1 and
γ1 chains into a coiled-coil α helix. At the carboxy-
terminus the additional G domains of the α1 chain are
separately folded into 5 globes (Beck et al. 1990).
Folding of the chains into a restricted repertoire of
Among the many potential α?β?γ combinations
between known chains, there is so far in vivo evidence
of only 11 different heterotrimers (Fig. 2). Why all
combinations are not possible is unclear; certain
trimers may have a higher stability than others
depending on the strength of the ionic interactions
between the chains (Beck et al. 1993); alternatively, a
given cell, at a given time, may specifically synthesise
only a restricted and appropriate repertoire of laminin
All 5 variants of the α chain have been shown or
predicted to associate with the γ1 and either the β1 or
the β2 chain, the latter being a similar size variant of
the β1 chain. Two shorter chains, β3 and γ2, appear to
associate exclusively with the α3 chain (Fig. 2).
However, due to difficulties in their isolation, only 5
forms of the intact trimers, laminins 1, 2, 4, 5 and 6,
have been purified.
Structure of other laminin isoforms
Based on sequence data, and on theoretical stability
(Beck et al. 1993) it is speculated that combinations of
full-length chains into α?β?γ trimers should result in
molecules adopting an overall domain structure and a
shape similar to that of laminin 1 (Beck et al. 1993).
This agrees with electron microscopy observations
showing particles similar to those of laminin 1 in
preparations containing laminins 2 and 4 (Paulsson &
Saladin, 1989; Brown et al. 1994). Interestingly, for
laminins extracted from mouse heart (Paulsson &
Saladin, 1989), or bovine kidney (Lindblom et al.
1994) one of the short arms is longer than those of
laminin 1; it could indicate the presence of laminin 10
or 11 containing the α5 chain (Miner et al. 1995, 1997)
which is predicted to be longer than the α1 or the α2
chain. By contrast, rotary-shadowed laminin 5 or 6
appear in electron microscopy, respectively, as a long
rod flanked by globular ends (Rousselle et al. 1991),
and as Y-shaped particles (Marinkovich et al. 1992a),
Laminins and basement membrane function
in agreement with sequence data indicating chain
truncation. Preparations containing the α4 chain
associated with β1 or β2, and with the γ1 chains
should also be seen as Y-shaped particles.
The prediction that a large portion of the α, β and
γ chains are folded into α helix agrees with the circular
dichroism spectra observed for laminins 1, 2, 4 and 5
(Ott et al. 1982; Paulsson et al. 1987a; Lindblom et al.
1994; Rousselle et al. 1995) demonstrating that α
helical structures account for about 30% of the
conformation. The stability of the coiled-coil fold
varies between laminin isoforms, with melting tem-
perature Tm of 72 ?C (Rousselle et al. 1995), 64 ?C
(Lindblom et al. 1994) and 58 ?C (Ott et al. 1982;
Paulsson et al. 1987a), for laminin 5, laminins 2 and
4, and laminin 1, respectively. This may reflect
differences in the strength of the ionic interactions
between the chains of laminin adapted to specific
A more detailed structural picture of laminins
should be soon available due to rapid progress in the
production of recombinant laminin fragments and in
solving their structure by -ray crystallography and
NMR, as has already been done with 3 LE motifs of
the laminin γ1 chain (see below).
Laminin chains are distinct gene products (Martin &
Timpl, 1987; Tryggvason, 1993). Variability in the
sequences and in the modular organisation of the
different molecules has presumably evolved from
Fig. 3. General rules and major steps for laminin heterotrimer synthesis and secretion.
duplication and reshuffling of an ancestralgene during
evolution. Based on sequence similarities, the laminin
α5 chain is the closest to the only known laminin α
chain in Drosophila (Miner et al. 1995). Alternative
splicing of the mRNA has so far been detected for the
α3 chain (Ryan et al. 1994, Galliano et al. 1995, Miner
et al. 1997). For another chain, α5, it is not clear
whether there are alternative spliced variants or
processed chains (Miner et al. 1997; Sorokin et al.
The α?β?γ trimers are formed intracellularly
through several steps, including chain selection,
assembly, and stabilisation (Fig. 3). Positioning in
register of appropriate chains may be driven by
recognition sequences and ionic interactions between
the 3 chains (Beck et al. 1993). First, a 10-residue
peptide localised to the C-terminal region of the
laminin γ1 chain is probably crucial for the formation
of stable, disulphide-linked β?γ dimers (Utani et al.
1994; Yurchenco et al. 1997; for review see Maurer &
Engel, 1996). Subsequent incorporation of the α chain
could be controlled by sequences located in the
amino-terminal portion of domain II (Niimi &
Kitagawa, 1997), and drives secretion of the hetero-
trimers (Yurchenco et al. 1997). Assembly and
stabilisation by disulphide bonds are likely to be
required for translocation of the heterotrimers from
the endoplasmic reticulum to the Golgi complex for a
complicated glycosylation, before transfer to the
extracellular space (Cooper et al. 1981).
Except for cleavage of the signal peptides, no
extracellular processing has so far been reported for
M. Aumailley and N. Smyth
the α1, β1, β2, or γ1 chains. In contrast, the C-
terminal regions of the α2 and α3 chains are probably
processed and the last 2 G domains, G4 and G5, are
cleaved off, although they may remain bound to the
rest of the molecules by disulphide bonds (Ehrig et al.
1990; Paulsson et al. 1991; Marinkovich et al. 1992a;
Burgeson, 1996). The amino-terminal portions of the
human α3 and γ2 chains are truncated by proteolytic
(Marinkovich et al. 1992b; Vailly et al. 1994). A more
extensive processing leading to a larger truncation has
been reported for the γ2 chain synthesised by a rat
tumour cell line (Giannelli et al. 1997).
respective domain III
The earliest studies on laminin chain expression and
extracellular deposition of the proteins showed that
laminin was a ubiquitous component of basement
membranes appearing at a very early developmental
stage of mouse embryos. The β1 and γ1 chains are
detected within cells at the 2–4 cell stage (Dziadek &
Timpl, 1985) and laminin containing the α1, β1 and γ1
chains is present extracellularly at the 16-cell stage,
while synthesis of collagen IV chains does not start
before the blastula stage (Cooper & MacQueen,
1983). In embryoid bodies which provide a model for
studying basement membrane formation, appearance
of extracellular laminin also coincides with α1 chain
expression and a linear immunofluorescence staining
(Tunggal & Aumailley, unpublished; Smyth et al.
unpublished). The crucial role of laminin in early
development has recently been confirmed by deletion
of the LAMC1 gene showing that absence of laminin
γ1 chain precludes the formation of laminin trimers
and of a basal lamina as well as the development of
embryos (Smyth et al. unpublished).
At later developmental stages and in adult tissues,
early studies failed to detect all of the 3 chains, in
particular the α1 chain, in some basement membranes
of laminin-expressing cells, raising the possibility of
the existence of laminin dimers lacking an α chain or
of alternative laminin chains. The former possibility
has now been excluded by the identification of new
laminin chains and by the use of better characterised
chain-specific reagents (antibodies, cDNA probes).
This has led to a more comprehensive picture of
laminin chain expression and distribution and has
permitted the resolution of several long-standing
controversies (see Ekblom, 1996; Tiger et al. 1997).
Nevertheless, an exhaustive picture of cell and time-
specific expression of laminin chains and of tissue-
specific deposition of laminin isoforms is at the
moment not available: our knowledge is restricted to
the chains for which precisely characterised reagents
have been developed. In spite of this, the following
general considerations are emerging. Laminin chain
expression is regulated, leading to tissue and de-
velopmental stage-specific localisation of isoforms.
Certain laminin chains are synthesised both by mes-
enchymal and parenchymal cells, while others are
produced exclusively by parenchymal cells (Simo et al.
1992; Thomas & Dziadek, 1993; Schuler & Sorokin,
1995; Tiger et al. 1997). Cellular expression of several
chains can overlap while expression of other comp-
exclusive, apparently depending on the stage of
development. This is the case for α1?α2, α1?α5, or
β1?β2 pairs (Engvall et al. 1990, Sanes et al. 1990;
Lentz et al. 1997; Miner et al. 1997; Sorokin et al.
1997; Tiger et al. 1997).
The laminin α1 chain is expressed by newly forming
epithelial cells. For example, during kidney devel-
opment it is present in proximal renal tubules and in
the glomerular mesangium, but not in the glomerular
or vascular basement membranes (Klein et al. 1988;
Ekblom et al. 1991; Virtanen et al. 1995). Laminin α2
chain is predominantly synthesised by mesoderm-
derived cells, including mesangial and myogenic cells
(Schuler & Sorokin, 1995; Sorokin et al. 1997) and α2
chain-containing isoforms are typically present in the
basal lamina of muscle and motor neuron synapses
(Engvall et al. 1990; Sanes et al. 1990). The laminin α3
and?or α5 chains are expressed by epithelial cells
(Ryan et al. 1994; Sorokin et al. 1997) and the
of mature epithelium (Sorokin et al. 1997). Laminin
α3 chain-containing isoforms occur in basement
membranes underlying stratified epithelial where they
are associated with the anchoring filaments orig-
inating at the hemidesmosomes and spanning the
lamina lucida towards the lamina densa and adjacent
anchoring fibrils (Rousselle et al. 1991; Marinkovich
et al. 1992a; Champliaud et al. 1996). The α5 chain
may have the broadest distribution, with deposition of
isoforms comprising this chain in kidney, heart,
muscle, and lungs (Miner et al. 1997; Tiger et al.
1997). Interestingly, the chain is synthesised by early
but not late myogenic cells and consequently it is not
found in mature muscle except at the neuromuscular
junction, suggesting that the laminin α5 chain could
play a role in myogenesis (Sorokin et al. 1997).
Synthesis of the α4 chain might be restricted to
endothelial cells (Sorokin et al. 1994). So, despite a
similar domain organisation common to all isoforms,
Laminins and basement membrane function
deposition of proteins suggest strongly a functional
Laminin polymerisation and network formation
Although network-forming collagen IV, an abundant
structural component of mature basement mem-
Fig. 4. Laminin polymerisation. (A) The model is based on the 3 arm-polymerisation hypothesis proposed for laminin 1 (Yurchenco &
Cheng, 1993). (B) Speculative model for potential polymerisation of laminin 5?6 dimers.
branes, endows the basal lamina with stability (Timpl
et al; 1981; Yurchenco & Schittny, 1990), laminin
plays an essential role in basement membrane for-
mation due to multiple interactions with itself and
In vitro, laminin 1 self-associates by means of
interactions between the amino-terminal globular
domains VI (Fig. 4) and forms grossly hexagonal
networks (Yurchenco et al. 1985, 1992). Polymeris-
ation is reversible and requires a minimal laminin
M. Aumailley and N. Smyth
concentration and divalent cations (Yurchenco et al.
1985; Paulsson, 1988). Cation-dependent polymeris-
ation probably explains why some laminins can be
extracted from tissues by using neutral buffers
containing chelating agents such as EDTA. This
assembly model was derived from studies with laminin
1, which contains 3 domain VI, 1 on each of the short
arms (Yurchenco & Chen, 1993). It also applies to
laminins 2 and 4 and can be reasonably extrapolated
to other isoforms with homologous domain organ-
isation (Cheng et al. 1997). Accordingly, basement
membranes containing the α1, α2, or α5 chains, or
possibly the α3B variant, associated with the β1 or β2
chain and the γ1 chain, may contain such calcium-
dependent laminin polymers. Indeed, isoforms such as
laminins 2, 4, and kidney laminins are rather easily
extracted from tissues with chelating agents. Similar
hexagonal assemblies were observed in situ, inde-
pendently of the presence of collagen IV networks
(Yurchenco et al. 1992). In vivo, initiation of laminin
polymerisation may, however, necessitates a ‘cata-
lytic’ event, such as clustering and trapping of the
molecules at the cell surface by laminin receptors.
Such an assembly model, however, might not apply
to every laminin isoform, in particular to those
containing the α3, α4, or γ2 chains which lack domain
VI (Cheng et al. 1997). An alternative assembly
pattern has been found for α3 chain-containing
isoforms, laminins 5, 6 and 7, which form dimers by
establishment of a disulphide bond between the
amino-terminal region of laminin 5 with that of
laminin 6 or 7 (Champliaud et al. 1996). Laminin 5
has only a single domain VI on the β3 chain, while
laminins 6 or 7 have 2, one contributed by the β1 or
β2 chain, respectively, and another by the γ1 chain, so
that laminin 5?6 or 5?7 dimers contain 3 domains VI
of laminin polymerisation (Yurchenco & Cheng,
1993), the dimers could, theoretically, self-associate,
but it remains to be demonstrated. Moreover, it is not
known whether in vivo laminin polymers are hom-
ologous or heterologous in term of isoforms, although
laminins 1 and 2 copolymerise in vitro (Cheng et al.
1997). For other extracellular matrix components
such as the fibrillar collagens it is well established that
mixing varying proportions of several collagen types
Rest & Bruckner, 1993). If this would be the case for
laminins, a large structural and biological diversity in
the networks could be achieved. Superimposition and
intertwining of the laminin and collagen IV networks
may define the degree of porosity and the filtration
function of basement membranes. Length variations
in the laminin short arms as occurs with different
isoforms may result in a greater size range in the
Short arm-mediated laminin interactions with other
extracellular matrix components—the case of nidogen
Besides self-assembly, the first strong evidence that
laminin was involved in protein–protein interactions
came from the observation that antibodies against
ponent,nidogen?entactin (Hogan etal.1980;Dziadek
& Timpl, 1985). Later, it was found that laminin 1 and
nidogen were extracted as a stable and equimolecular
complex from tissues (Paulsson et al. 1987a). Nidogen
is a smaller glycoprotein of 150 kDa with 2 amino-
terminal globular domains, G1 and G2, separated by
a short stretch of amino acids, a central rod-like
domain constituted by the repetition of 5 EGF-like
motifs (with 6 cysteine residues), and 1 globular
domain, G3, at the carboxy-terminus (Fox et al.
1991). The laminin-nidogen complex is formed upon
a high affinity interaction, Kd?0?5 n, between an
LE motif in domain III of the laminin γ1 chain,
γ1III4, and the carboxy-terminal G3 domain of
nidogen (Fox et al. 1991; Gerl et al. 1991; Mayer et al.
1993). Structure and conformation of the γ1III4 and
adjacent motifs have now been clarified by nuclear
magnetic resonance and -ray crystallography analy-
ses which show that the motifs are separately folded
and that critical residues for nidogen binding are
(Baumgartner et al. 1996, Stetefeld et al. 1996).
By its amino-terminal G2 domain, nidogen binds to
collagen IV (Aumailley et al. 1989), or to perlecan, the
main heparan sulphate proteoglycan of basement
membranes (Battaglia et al. 1992; Reinhardt et al.
1993). Despite the fact that collagen IV and laminin
do not directly interact (Aumailley et al. 1989) the
formation of ternary complexes permits connection of
the 2 major networks (Fig. 5). Ten out of the 11
identified laminin isoforms contain the γ1 chain and
can potentially interact with nidogen. This has been
confirmed by direct binding studies of nidogen to
laminin 2 and 4 (Brown et al. 1994) and is indirectly
implied by the presence of nidogen together with
laminins in EDTA-extracted material from different
tissues (Paulsson & Saladin, 1989; Lindlbom et al.
1994). The physiological relevance of the interactions
between laminin and nidogen has been confirmed by
the nidogen binding site on laminin γ1 chain which
Laminins and basement membrane function
separately, but could be superimposed.
dramatically perturb branching epithelial morpho-
genesis (Kadoya et al. 1997).
The one exception to nidogen-mediated interactions in
In one isoform, laminin 5, the γ1 chain is replaced by
the γ2 chain, which, despite high sequence identity in
the γ2III4 motif, has negligible binding to nidogen
due to replacement of a single crucial amino acid
(Mayer et al. 1995; Po ? schl et al. 1996). Integration of
γ2 chain-containing isoforms within the architec-
tural scaffold of basement membrane is, however,
achieved by other specific interactions. Laminin 5 is
restricted to a subset of basement membranes under-
lying squamous epithelia, such as in skin where it is
localised to the anchoring filaments connecting hemi-
desmosomes to the basal lamina and adjacent
anchoring fibrils. Laminin 5 or the laminin 5?6 dimer
interacts with collagen VII (Chen et al. 1997;
Rousselle et al. 1997), which is the major component
of the anchoring fibrils (Bruckner-Tuderman, 1991;
Burgeson, 1993). Collagen VII has a long and flexible
triple helix (450 nm) and a large noncollagenous
domain, NC1, contributed by the amino-terminus of
the 3 α1(VII) chains separately folded into 36 nm
arms (Bruckner-Tuderman, 1991; Burgeson, 1993),
which contain several motifs potentially involved in
protein–protein interactions (Parente et al. 1991;
Christiano et al. 1992). Interestingly, the data indicate
that collagen VII probably binds to laminin 5 only
(Fig. 5) and not to laminin 6 which implies that the
interaction occurs either with the β3 or γ2 chain, but
not with the α3 chain (Rousselle et al. 1997). The NC1
domain of collagen VII also interacts with collagen IV
(Burgeson, 1993), and probably with other com-
ponents such as the recently identified GDA-J?F3
antigen, a small 45–50 kDa protein (Gayraud et al.
Based on the colocalisation in the anchoring
filaments of laminin 5 (Rousselle et al. 1991) and
collagen XVII (Masunaga et al. 1997), it is speculated
that they interact although experimental evidence is
still lacking. The amino acid sequence deduced for
collagen XVII predicts a transmembrane protein
where the carboxy-terminal portion is extracellular
(Li et al. 1993). From sequence data the human
ectodomain is presumably folded into 15 interrupted
collagen helices interspaced by small noncollagenous
sequences (Li et al. 1993; Balding et al. 1997). On
electron microscopy, rotary-shadowed particles ap-
pear as a 60–70 nm rod and a 100–130 nm flexible tail
(Hirako et al. 1996). Collagens associate in homo or
heterotypic oligomers or polymers through inter-
actions between their triple helices (van der Rest &
Garonne, 1992; Brown & Timpl, 1995). The helical
rods of collagen XVII adjacent to the cell membrane
could, therefore, laterally interact and the distal C-
terminal interrupted and hence flexible collagenous
region could interact with other basement membrane
components such as laminin 5.
Support for these speculations is provided by
investigations of several human diseases of the skin
showing that the interactions of laminin 5 with other
components of the basal lamina are crucial for
basement membrane stability as highlighted by the
phenotypes developed by patients with inborn defects
M. Aumailley and N. Smyth
in the genes coding for laminin 5, collagen VII, or
collagen XVII chains or with autoimmune disorders
Additional and long arm-based interactions of
laminins with other extracellular components
Laminin 1 fragment E3 (G4–G5 domains) has heparin
binding activity (Ott et al. 1982), which may con-
tribute to perlecan binding to laminins. Perlecan has a
large protein core (480 kDa) with a single polypeptide
folded into 5–6 globular domains aligned in a 80 nm
long row and has 3 heparan sulphate chains connected
at one end (Paulsson et al. 1987b). The predicted
amino acid sequence of the protein core has structural
homology to the laminin α chains (several EGF-like
motifs separated by cysteine-poor regions, and
sequences analogous to that of the G domains), the
receptor (Noonan et al. 1991). The extended shape of
perlecan may allow binding to the laminin-nidogen
complex via the nidogen G2 domain as well as direct
binding of the heparan sulphate chains to the laminin
1 fragment E3 (Battaglia et al. 1992). Interestingly,
there is no direct binding of perlecan to laminin 2 or
4, which indicates that the laminin α1 and α2 chains
differ functionally (Brown et al. 1994). Interaction
with laminin was observed for other heparan sulphate
proteoglycans, the agrins, which have structural
homology with perlecan and laminin α chains (Rupp
et al. 1991; Ushkaryov et al. 1992; Tsen et al. 1995).
Agrins exist in active and inactive forms displaying
binding proficiency for β2 and to a lesser extent to the
β1 laminin chains, whereas the inactive form of agrin
binds more strongly to α-dystroglycan than the active
counterpart (Hopf & Hoch, 1996; Denzer et al. 1997).
Two other proteins, fibulins 1 and 2, which are not
restricted to basement membranes, may be directly or
indirectly involved in laminin interactions and in its
connection with the underlying stroma (Timpl, 1996;
Tran et al. 1997). Both fibulins bind to nidogen or
fibronectin with high affinity and to several other
extracellular matrix molecules with lower affinity
(Sasaki et al. 1995a, b). The fibulins, however, have,
different connecting functions. Fibulin 1 binds to the
nidogen G2 domain and could therefore connect the
laminin network to the stroma via fibronectin, while
fibulin 2 binds to the nidogen G3 domain and
therefore could compete with laminin binding to
nidogen (Sasaki et al. 1995a). Furthermore, fibulin 2
interacts with domain IV of the laminin γ2 chain and
to a peptide sequence of the laminin α1 chain (Utani
et al. 1997) making
connections. This is at variance with previous results
showing no binding of fibulin 2 to laminin 1 (Sasaki et
al. 1995a). Here it is interesting to note that it has
been proposed that domain IV of the laminin γ2 chain
is removed during processing of the chain (Vailly et al.
1994) and the relevance of this binding needs to be
Although not integral basement membrane com-
ponents, many other molecules including proteases
(Moser et al. 1993), serum amyloid A (Ancsin &
Kisilevsky, 1997) and P (Zahedi, 1997), and growth
factors have the propensity to bind to laminins, and
may affect their functions in the context of a basement
membrane. The multiple interactions of laminin with
itself and with other basement membrane constituents
presumably regulate their biological activity by
affecting the conformation and the spatial orientation
of the different components and of their subdomains.
possible additional inter-
Soon after discovery, EHS laminin (laminin 1) was
shown to have cell adhesion-promoting activity
(Terranova et al. 1980) which triggered a huge amount
of research work. It is now well established that
laminins are endowed with the property of controlling
directly or indirectly cellular activities such as adhe-
sion or migration, differentiation and polarity, prolif-
eration or apoptosis, and gene expression. The use of
proteolytic fragments and of synthetic or recombinant
(poly)peptides replicating portions of laminins led to
a mapping of several cell binding sequences or
Diverse integrin binding sites on laminins
The first cell adhesion site described for laminin 1
corresponds to the pepsin-resistant fragment P1
(200 kDa), originating from the centre of the cross
formed by the 3 short arms and lacking most of the
globular domains (Ott et al. 1982; Rao et al. 1982;
Timpl et al. 1983). An RGD sequence located on one
LE motif of domain IIIa of the mouse laminin α1
chain is responsible for the activity (Aumailley et al.
1990a). The sequence is, however, cryptic in native
laminin 1 and, at least in vitro, becomes accessible to
cells only after proteolytic degradation of the adjacent
domain IVa (Nurcombe et al. 1989; Aumailley et al.
1990b). In the human laminin α1 chain the sequence
is RAD and has not been proven to be active. From
the deduced amino acid sequence it can be predicted
Laminins and basement membrane function
that the tripeptide is probably localised at the apex of
a disulphide-linked loop of the LE motif. Fragment
P1 is the target for several promiscuous RGD-binding
integrins such as αvβ1 or αvβ3 (Aumailley et al.
1990b; Kramer et al. 1990; Sonnenberg et al. 1990;
Goodman et al. 1991).
Thelaminin 1 shortarmscontains other cell binding
sites available to cells on the intact molecule (Hall et
al. 1990; Tomaselli et al. 1990; Goodman et al. 1991),
and one has been mapped to domain VI (Colognato-
Pyke et al. 1995). Cellular interactions with intact
laminin 1 short arms are RGD-independent and
mediated by the classical collagen binding integrins,
α1β1 or α2β1 (Languino et al. 1989; Goodman et al.
1991; Pfaff et al. 1994; Colognato-Pyke et al. 1995).
Whether similar integrin binding sites exist on the
short arms of other isoforms is controversial. By
direct receptor-ligand binding assays no interactions
were detected between the α1β1 or α2β1 integrins and
laminins 2 or 4 (Pfaff et al. 1994), while in cell
adhesion inhibition assays these 2 integrins were
involved in the recognition of recombinant domain VI
of the laminin α2 chain (Colognato et al. 1997).
The major cell binding domain of laminin 1
corresponds to the proteolytic fragment E8 (240 kDa)
which consists of the carboxy terminal part of the
triple-stranded helix formed by the α1, β1 and γ1
chains and by the G1 to G3 domains of the α1 chain
(Aumailley et al. 1987; Goodman et al. 1987).
Unfolding of fragment E8 coil-coiled conformation or
proteolytic cleavage between the rod and the G
domains leads to, respectively, partial or complete loss
of the cell adhesion activity, without cell spreading
(Deutzmann et al. 1990). Similarly, the activity of
recombinant G domains did not reproduce that of
native laminin (Sung et al. 1993; Mizushima et al.
1997) and a reactivity similar to that of the authentic
molecule was restored only after reconstruction
of a coil-coiled fold (Sung et al. 1993). Helical
conformation-dependency of cell binding activity is so
far a characteristic feature of other investigated
laminin isoforms, including laminins 2 and 4 (Brown
& Goodman, 1991; Champliaud, Beck & Aumailley,
unpublished), laminin 5 (Rousselle et al. 1995), and of
the laminins extracted from bovine kidney (Dogic et
al. unpublished). The current interpretation is that the
cell binding site is located on the G domain which, for
correct folding, requires the presence of the adjacent
helical rod. These complex requirements highlight the
crucial role of folding of noncontiguous sequences on
the spatial organisation and consequent biological
activity of adhesion motifs, which has impaired efforts
to ascribe the cell binding site at the amino acid level.
Fig. 6. Mapping of cell binding sites on laminin 1. The laminin
proteolytic fragments with biological activity as well as the
corresponding receptors are indicated.
In contrast, the integrins involved in these inter-
actions have been identified (Fig. 6). Integrins are cell
surface receptors involved in the bidirectional transfer
of information between the extracellular matrix and
the cell interior (Hynes, 1992; Clark & Brugge, 1995).
Several integrins have the property of binding
laminins and it is logical to assume that they are
involved in specific mechanical functions and sig-
nalling. To recognise the long arm of laminin 1, most
cells use the α6β1 integrin (Aumailley et al. 1990a, b;
Sonnenberg et al. 1990) while certain cells, such as
myoblasts or melanoma cells, use the α7β1 integrin
(Kramer et al. 1991; von der Mark et al. 1991). Other
laminin isoforms are also ligands for the α6β1 integrin
and, in addition, for the α3β1 integrin (Carter et al.
1994; Dogic et al. 1998). Several sets of data indicate
that the affinities of these 2 integrins vary between
isoforms which suggests that the adhesion motifs are
not strictly identical. Identification of α3β1 integrin
ligands as well as their role is still controversial.
Initially,α3β1integrinwas identifiedasa promiscuous
receptor for several extracellular matrix proteins,
including laminin, fibronectin, and collagens (Takada
et al. 1991; Hynes, 1992), but later studies indicated a
specificity restricted to laminin isoforms, except
laminin 1 (Carter et al. 1991; Sonnenberg et al. 1991b;
Delwel et al. 1994; Rousselle & Aumailley, 1994).
Alternatively, interaction of the α3β1 integrin with
certain ligands may require stabilisation by an as yet
unknown mechanism (DiPersio et al. 1995). By its in
vivo localisation at the basal surface of basal
keratinocytes, another integrin, α6β4 (DeLuca et al.
1990; Sonnenberg et al. 1991a), is potentially involved
in cell anchorage to laminins. However, most in vitro
M. Aumailley and N. Smyth
studies have failed to demonstrate a distinct binding
of this integrin to laminins (Sonnenberg et al. 1990;
for review, see Aumailley et al. 1996). The affinity
between α6β4 integrin and laminin may be too low to
be seen in vitro, when other high affinity integrins are
present on the cells. Alternatively, α6β4 integrin
binding may need stabilisation or induction by other
integrins (Rousselle & Aumailley, unpublished).
Functional specificity of laminin-binding integrins
It has been shown that α3β1 and α6β4 integrins
participate in different anchorage processes between
the extracellular matrix and, respectively, the actin or
keratin-based cytoskeleton (Carter et al. 1990;
Niessen et al. 1997). Specifically, the α6β4 integrin is
thought to mediate stable anchorage of cells to
laminins (Carter et al. 1990), in agreement with the
fact that keratinocytes lacking the β4 integrin chain
have an increased motility (Niessen et al. 1996), while
the α3β1 integrin may play a role in matrix assembly
as inferred by the phenotype of α3 integrin chain-
deficient mice, presenting, in particular, with a
disorganisation of the kidney and skin basal lamina
(Kreidberg et al. 1996; DiPersio et al. 1997). The α6β1
integrin is presumably involved in epithelial cell
polarisation (Sorokin et al. 1990). Moreover, unique
signalling pathways could be triggered by these
integrins since activation of α3β1 or α6β4 correlates
with phosphorylation or stimulation of different
proteins (Jewell et al. 1995; Wary et al. 1996; Xia et al.
1996; Mainiero et al. 1997).
Non-integrin-mediated cellular interactions with
A minor cell binding site was assigned to the laminin
1 heparin binding fragment E3 (Fig. 6) which
corresponds to the last 2 carboxy terminal G domains
(Sonnenberg et al. 1990; Taraboletti et al. 1990;
Gehlsen et al. 1992; Sorokin et al. 1992). Its
interaction with cells is integrin-independent and is
perturbed by heparin (Sorokin et al. 1992). The
interaction is probably mediated by α-dystroglycan, a
component of the dystrophin-glycoprotein complex
(Henry & Campbell, 1996), since in protein–protein
binding assays purified α-dystroglycan binds to frag-
ment E3 (Gee et al. 1993; Cohen et al. 1997) and
antibodies against α-dystroglycan perturb the ad-
hesion of schwannoma cells to laminin 1 (Matsumura
et al. 1997). The α-dystroglycan-mediated cellular
interactions may be laminin isoform-specific. While
the binding of skeletal α-dystroglycan to laminin 1 or
to a mixture of laminins 2 and 4 is similar, heparin
inhibits binding to laminin 1 to a greater extent than
that to the laminins 2?4 mixture. However, binding of
brain α-dystroglycan to both laminin preparations is
inhibited by heparin to the same extent, indicating
that the binding of different forms of α-dystroglycan
to laminins may be specifically regulated (Pall et al.
1996). Moreover, the adhesive forces developed on
laminin 2 by dystrophic myotubes are reduced in
comparison to that of normal myotubes while they are
similar on laminin 1 (Angoli et al. 1997).
The dystroglycan–laminin interactions are import-
ant for branching epithelial morphogenesis such as in
kidney, lung, or salivary gland, since function-
blocking antibodies against α-dystroglycan or against
the most carboxy-terminal G domains (fragment E3)
of the laminin α1 chain perturb the branching process
(Sorokin et al. 1992; Durbeej et al. 1995; Durbeej &
Ekblom, 1997). α-dystroglycan is linked to β-
dystroglycan which itself is a transmembrane poly-
peptide anchored to dystrophin or its homologues
(Henry & Campbell, 1996). The cytoplasmic domain
of β-dystroglycan contains several motifs with a
potential role in signal transduction, including a
phosphotyrosine consensus sequence and several
proline-rich regions (Ibraghimov-Beskrovnaya et al.
Several galectins (Barondes et al. 1994) interact
with laminins and may control the spreading and the
migration of cells on specific domains of laminins
(Hall et al. 1997). The exact mechanisms of these
effects as well as the ligand binding sites are unclear.
Several synthetic peptides from the laminin α1, β1, β2,
or γ1 chains, also affect cellular interactions with
laminin (Nomizu et al. 1997, and included references),
but it remains to be shown whether they merely
perturb cell surface receptors or really mimic the
activity of theauthentic
(Brandenberger et al. 1996).
Themajorchallenge isto ascribe the in vivo functional
relevance of the multiple interactions of laminins
which have been observed in vitro. In particular, a
major issue is to determine under physiological or
pathological conditions which laminins or other
basement membrane molecules and which integrins or
other cell surface associated components are involved
in cellular interactions and in the control of the cell
Laminins and basement membrane function
Fig. 7. The diverse modalities of laminin interactions with cell surface receptors. It is likely that several of the interactions shown occur
phenotype (Fig. 7). There is a growing list of inborn
human or animal diseases and site-directed mutations
in mice which affect basement membrane functions
due to deficiencies in either laminins or their receptors.
These animals and cell lines derived from them have
and will allow linkage of in vitro data and in vivo
function. There are also acquired diseases where
autoantibodies presumably perturb one or several of
the interactions that laminin develops with itself or
Embryonically lethal conditions
Based on the early expression of the laminin α1 and
the ubiquitous expression of the laminin β1 and γ1
chains, it was speculated that mutation causing
absence or highly altered structure of these chains
would be lethal. This has been confirmed by deletion
of functional LAMA or LAMC1 gene in, respectively,
drosophila (Henchcliffe et al., 1993) and mouse
(Smyth et al. unpublished), both conditions leading to
early embryonic lethality (Table 1). Similarly, targeted
extinction of the ITGB1 gene coding for the β1
integrin chain is not compatible with embryonic
development and leads to peri-implantation lethality
(Fa ? ssler et al. 1995; Stephens et al. 1995). This is
probably the reason why there is no known disease
associated with mutations in these polypeptide chains
and these observations strengthen the absolute pre-
requisite of functional laminin and laminin-integrin
interactions for embryonic development.
Laminin and integrin defects affecting the epidermal-
dermal junction: epidermolysis bullosa junctionalis
In man, a subset of skin blistering diseases, the
junctional types of epidermolysis bullosa, are due to
the absence or the alteration of the laminin α3, β3 or
γ2 chains or of the integrin α6 or β4 chains (see Table).
At an ultrastructural level these genodermatoses are
characterised by abnormality in, or an absence or
reduced numbers of hemidesmosome-anchoring fila-
ment complexes. These specialized structures of the
epidermal-dermal junction secure the epidermis to
the upper layer of the basement membrane (Eady,
1986). At sites of friction or after minor trauma, the
patients develop a split within the lamina lucida
at the epidermal-dermal junction. The alterations
result in complications leading most frequently to
death perinatally or in early infancy. According to the
severity of the symptoms, several subgroups have
been defined suggesting that different molecular
defects underlie these pathologies (Fig. 8). In the most
severe cases, the lethal Herlitz type, mutations leading
to absence, instability, or truncation of the RNA have
been identified in the human genes coding for the α3,
β3, or γ2 laminin chains (see Table for references).
Disruption of the LAMB3 gene coding sequence
produces a phenotype of junctional epidermolysis
bullosa also in a spontaneous mouse mutant (Kuster
et al. 1997). When the laminin α3 chain is absent
laminins 5 and 6 cannot be formed, while mutations
precluding the presence of the β3 or γ2 chains prevent
laminin 5, but not laminin 6, expression (Fig. 8).
However, the clinicaland
pictures are similar in all 3 conditions, indicating
that laminin 6 cannot compensate for the lack of
mechanical function associated with the absence of
Absence or truncation of the α6β4 integrin (Fig. 8),
a laminin 5 receptor, caused by mutations in the
human ITGA6 or ITGB4 gene, is also associated with
M. Aumailley and N. Smyth
Table. Mutations or extinction of genes with consequences on laminin-related basement membrane functions
Gene SpeciesPhenotype References
Viable, progressive CMD
Henchcliffe et al. 1993
Tome? et al. 1994
Helbling-Leclerc et al. 1995
Nissinen et al. 1996
Allamand et al. 1997
Guicheney et al. 1997
Sunada et al. 1994
Xu et al. 1994
Miyagoe et al. 1997
Kivirikko et al. 1995
McGrath et al. 1995b
Noakes et al. 1995a, b
MouseViable, progressive MD
LAMA3Human Perinatal death, JEB
absence of anchoring filaments
Defects of the GBM and of the
Perinatal (JEB) or early
infancy death (GABEB)
LAMB3 HumanMcGrath et al 1995a
Pulkkinen et al. 1994a
Vailly et al. 1995a
Kuster et al. 1997
Smyth et al. unpublished
Pulkkinen et al. 1994b
Aberdam et al. 1994
Baudoin et al. 1994
Vailly et al. 1995b
Epidermal?dermal split (JEB)
Perinatal death, JEB
absence of anchoring filaments
ITGA3Mouse Disorganisation of basal laminaKreidberg et al. 1996
DiPersio et al. 1997
Ruzzi et al. 1997
Pulkkinen et al. 1997a
George-Labouesse et al. 1996
ITGA6Human Epidermal?dermal split (PA-
Perinatal death, JEB
Viable, progressive MD
Mayer et al. 1997
Stephens et al. 1995
Fa ? ssler et al. 1995
Vidal et al. 1995
Brown et al. 1996
Niessen et al. 1996
Pulkkinen et al. 1997b
Takizawa et al. 1997
Van der Nuet et al. 1996
Dowling et al. 1996
ITGB4 HumanEpidermal?dermal split (PA-
MousePerinatal death, JEB
CMD, congenital muscular dystrophy; JEB, epidermolysis bullosa junctionalis; PA-JEB, pyloric atresia associated with JEB; GBM,
glomerular basement membrane; GABEB, generalized atrophic benign epidermolysis bullosa.
a phenotype of epidermolysis bullosa with, in ad-
dition, pyloric atresia (see Table for references). In
mice, targeted disruption of the ITGA6 or ITGB4
genes produces apparently normally developing
fetuses, which at birth present a phenotype of
junctional epidermolysis bullosa with extensive epi-
dermal detachment causing perinatal death (see Table
for references). Except for the absence or abnor-
malities of the hemidesmosomes and some necrotic
areas, probably due to detachment, the morphology
and differentiation of the epidermal cell layers are
apparently normal (George-Labouesse et al. 1996). It
suggests that interactions between laminin 5 and
integrin α6β4 are not required for keratinocyte
differentiation and that other molecules compensate
for the loss of function. When another component of
the hemidesmosomes, collagen XVII, is defective, a
somewhat milder phenotype of generalised atrophic
benign junctional epidermolysis bullosa (GABEB) is
observed (McGrath et al. 1995c). With its trans-
membrane localisation and elongated shape, collagen
XVII could help to anchor basal epithelial cells to the
basement membrane. In addition, its intracellular
domain contains several potential phosphorylation
sites (Li et al. 1993) and this collagen may function as
a signal transducer and play a partial compensatory
role when laminin 5 or α6β4 integrin are absent
Deletion of the ITGA3 gene, leading to the absence
of another laminin receptor, the α3β1 integrin, causes
Laminins and basement membrane function
Fig. 8. Gene defects and lack of proteins in different subtypes of junctional epidermolysis bullosa.
a different phenotype with disorganisation of the
basal lamina in kidney, lung and skin, microblisters
and death from renal failure (Kreidberg et al. 1996;
DiPersio et al. 1997).
Several acquired cutaneous blistering diseases are
linked to the presence of autoantibodies against
antigens of the hemidesmosome-anchoring filament
complexes, such as collagen XVII and laminin 5
(Domloge-Hultsch et al. 1992; Shimuzu et al. 1995;
pemphigoid is characterised by the presence of
autoantibodies directed against the C-terminus of
collagen XVII. Since the carboxy-terminal end of
collagen XVII colocalises with laminin 5 (Bedane et
al. 1997; Masunaga et al. 1997), the antibodies could
impair interactions between the 2 proteins, and
consequently induce the loss of cohesion between
dermis and epidermis.
In conclusion, laminin 5 and its interactions with
other extracellular or transmembrane molecules are
most important for the architecture and the stability
of the basement membrane at the epidermal–dermal
junction, and it seems that there is no redundancy for
this specific mechanical function. By contrast a
redundancy may exist for signal transduction im-
pinging on cellular behaviour such as differentiation.
Laminin 5 is the major isoform of the dermo-
epidermal junction while laminin 6 and probably
other isoforms are present at a lower quantity. The
mechanical properties associated with laminin 5 may
rely on its high concentration and, when absent, the
lower concentration at which the other variants are
present may not be sufficient to compensate for the
loss of mechanical strength but may be enough to
trigger intracellular signalling and regulate cellular
Laminin and laminin receptor defects in congenital
muscular dystrophy and at the neuromuscular
Half of the patients with congenital muscular dys-
trophy present many splice site, nonsense, or missense
mutations of the LAMA2 gene, leading to absence,
M. Aumailley and N. Smyth
altered expression, or truncation in domain IVa or VI
of the laminin α2 chain (see Table for references).
Absence of laminin α2 chain, either spontaneously in
the dy?dy mouse (Sunada et al. 1994; Xu et al. 1994)
or by targeted gene disruption (Miyagoe et al. 1997),
or absence of the α7β1 integrin in α7 integrin subunit-
null mice (Mayer et al. 1997) lead to early and
progressive muscular dystrophy. A reduction of
laminin α2 chain expression is also observed in the
Fukuyama-type of muscular dystrophy, where the
deficiency in laminin is, however, secondary (Arahata
et al. 1997). Laminins containing the α2-chain are
present in the muscle basement membrane where,
through interactions with α7β1 integrin and α-
dystroglycan, they are involved together with dystro-
phin and other associated molecules in the architec-
ture of an important transmembrane complex of
proteins (Henry & Campbell, 1996). The muscular
weakness associated with the disease emphasises the
role of laminin and its interactions with itself or other
molecules in the stability and strength of the basement
membrane (Vachon et al. 1997). Absence of dystro-
glycan is, however, much more deleterious than
absence of laminin α2 chain or integrin α7 subunit
since Dag1-null embryos present a disruption of
Reichert’s membrane and die around 6?5 d of ges-
note that the loss of laminins 2 or 4 and of α7β1
integrin, but not that of dystroglycan, is compatible
with viability. Integrity of the neuromuscular junction
is also impaired in laminin β2 chain-null mice (Noakes
et al. 1995a, b). In these mice there are also alterations
there is probably partial compensation by the laminin
Laminins and their receptors are presumably
involved in other pathologies affecting the basement
membranes, such as diabetes, or the invasive growth
and metastasis of tumours. Here several concepts
have already been developed but due to their
complexity the molecular mechanisms underlying
these disorders are not yet elucidated. Improving our
knowledge of structural biology of laminins will
certainly help in solving the pathogenetic mechanisms
involved in these multifactorial diseases.
The authors gratefully acknowledge support of their
research by the Centre National de la Recherche
gemeinschaft (M.A.), the University of Cologne
(M.A. and N.S.), the BMFT and ZMMK (N.S.).
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