Pathologie Biologie 53 (2005) 430 442
http://france.elsevier.com/direct/PATBIO/
The collagen superfamily:
from the extracellular matrix to the cell membrane
La superfamille des collagŁnes :
de la matrice extracellulaire ą la membrane cellulaire
Sylvie Ricard-Blum *, Florence Ruggiero
Institut de Biologie et Chimie des Prot�ines, UMR 5086 CNRS UCBL, IFR128 Biosciences Gerland, 7, passage du Vercors, 69367 Lyon cedex 7, France
Received 26 November 2004; accepted 10 December 2004
Available online 20 January 2005
Abstract
The collagen superfamily is highly complex and shows a remarkable diversity in molecular and supramolecular organization, tissue dis-
tribution and function. However, all its members share a common structural feature, the presence of at least one triple-helical domain, which
corresponds to a number of (Gly X Y)n repeats (X being frequently proline and Y hydroxyproline) in the amino acid sequence. Several
sub-families have been determined according to sequence homologies and to similarities in the structural organization and supramolecular
assembly. In the present review, we focus on the newly described fibrillar collagens, fibrillar-associated collagens with interrupted triple helix,
membrane collagens and multiplexins. Recent advances in the characterization of proteins containing triple-helical domains but not referred
to as collagens are also discussed.
� 2005 Elsevier SAS. All rights reserved.
R�sum�
La superfamille des collagŁnes est particuliŁrement complexe et pr�sente une remarquable diversit� tant au niveau de l organisation mol�cu-
laire et supra-mol�culaire qu ą celui de la distribution tissulaire et des fonctions biologiques. N�anmoins, tous ses membres partagent une
caract�ristique structurale commune, la pr�sence dans leur structure d un domaine en triple h�lice qui correspond ą la r�p�tition du triplet
(Gly X Y)n (X �tant fr�quemment la proline et Y l hydroxyproline) dans la s�quence d acides amin�s. Les collagŁnes sont class�s en
plusieurs sous-familles d�termin�es en fonction des homologies de s�quence et de similitudes au niveau de l architecture modulaire des
cha�nes polypeptidiques et de leur assemblage supramol�culaire. L essentiel de cette revue est consacr� aux collagŁnes nouvellement identi-
fi�s qui sont des collagŁnes fibrillaires, des FACITs (associ�s aux collagŁnes fibrillaires), les collagŁnes membranaires et les multiplexines.
Cette revue inclut �galement une pr�sentation des prot�ines poss�dant au moins un domaine en triple h�lice mais non r�f�renc�s pour l instant
comme �tant des collagŁnes.
� 2005 Elsevier SAS. All rights reserved.
Keywords: Collagen; Collagen-related diseases; Extracellular domains; Modular proteins
Mots cl�s : CollagŁne ; Domaines extracellulaires ; Prot�ines modulaires ; Pathologies li�es au collagŁne
Abbreviations: BMP, bone morphogenetic protein; COL, collagenous domain; CRR, cystein-rich repeat domain; EMI, N-terminal cysteine-rich domain
found in the Emu family; Emu, Emilin and multimerin; Erk, extracellular-signal-regulated kinase; FAK, focal adhesion kinase; FACIT, fibril-associated colla-
gen with interrupted triple helix; FN3, fibronectin type III repeat; MARCO, macrophage receptor with collagenous structure, NC, non collagenous domain;
SR-Ai, SR-AII, scavenger receptors type A; TGF-b, transforming growth factor b; TSPN, thrombospondin N-terminal-like domain; vWA, von Willlebrand
factor A-like domain.
* Corresponding author.
E-mail address: [e-mail] (S. Ricard-Blum).
0369-8114/$ - see front matter � 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.patbio.2004.12.024
S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442 431
1. Introduction extracellular matrix proteins [1] and are thus modular pro-
teins. Since many collagen chains were initially character-
ized by partial sequencing, missing the sequences encoding
Collagens are trimeric molecules composed of three
the N-terminus of the protein, investigators in the field num-
polypeptide a chains, which contain the sequence repeat
bered these domains starting from the C-terminus. However,
(G X Y)n, X being frequently proline and Y hydroxypro-
the reverse order is also found in the literature for collagens
line. These repeats allow the formation of a triple helix, which
VII, XIII, XV, XVIII, XXII [2], XXIII [3], XXV [4] and XXVI
is the characteristic structural feature of the collagen super-
[5].
family. Each member of the collagen family contains at least
In this review, we will focus on recent advances in the field
one triple-helical domain (COL), which is located in the extra-
of collagens (Table 1). For a comprehensive coverage of the
cellular matrix, and most collagens are able to form supramo-
structure and functions of well-known collagens, the reader
lecular aggregates. However, some molecules such as emi-
is referred to previous reviews on fibrillar collagens [6],
lins, which do contain a collagenous domain and are
unconventional collagens including collagen VII, network-
associated with extracellular supramolecular assemblies (elas-
forming collagens (VI, VIII and X) and the fibril-associated
tic fibers), are surprisingly not classified as collagens.
collagen with interrupted triple helix (FACITs) (IX, XII, XIV,
Besides triple-helical domains, collagens contain non XVI and XIX) [7] and to recent reviews on the collagen super-
triple-helical (NC) domains, used as building blocks by other family [8,9].
Table 1
Swiss Prot or TrEMBL accession number (http://www.us.expasy.org/sprot/) are provided for non fibrillar a chains. Entries are provided for human proteins,
unless otherwise stated. For accession number of other collagen chains and collagen-like chains, the reader is refreed to previous reviews [6,7,9]
Les num�ros d accŁs Swiss Prot ou TrEMBL (http ://www.us.expasy.org/sprot/) sont fournis pour les cha�nes alpha non fibrillaires. Les entr�es sont fournies
pour les prot�ines humaines, ą moins qu il ne soit indiqu� autrement. Pour les num�ros d accŁs d autres cha�nes de collagŁne et les cha�nes collagŁne-like, le
lecteur doit se r�f�rer ą des revues ant�rieures [6,7,9].
Localization Collagen type Supramolecular assembly
Basement membrane associated Collagen IV
collagens
a1(IV) P02462
a2(IV) P08572
a3(IV) Q01955
a4(IV) P53420
a5(IV) P29400
a6(IV) Q14031
Collagen VIII Short chain collagen, hexagonal network
a1(VIII) P27658
a2(VIII) P25067
Collagen XV Multiplexin, supramolecular assembly unknown
a1(XV) P39059
Collagen XVIII Multiplexin, supramolecular assembly unknown
a1(XVIII) Q14035 TrEMBL
Membrane collagens Collagen XIII Type II membrane protein
a1(XIII)
Collagen XVII (BP180: 180 kDa Bullous Pemphigoid antigen 2) Type II membrane protein
a1(XVII) Q9NQK9
Q9UMD9
Collagen XXIII Type II membrane protein
a1(XIII) Q86Y22 TrEMBL
Collagen XXV (CLAC/P) (AMY protein) Type II membrane protein
a1(XXV) Q99MQ5 TrEMBL (Murine)
Ubiquitous Collagen VI Beaded filaments
a1(VI) P12109
a2(VI) P12110
a3(VI) P12111
Dermo-epidermal junction Collagen VII Anchoring fibrils
a1(VII) Q02388
Hypertrophic cartilage Collagen X Short chain collagen, hexagonal network
a1(X) Q03692
Ovary, testis Collagen XXVI (Emu2 protein, Emu-domain containing protein Supramolecular assembly unknown
2)
a1(XXVI) Q96A83
432 S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442
Fig. 1. Ultrastuctural analysis of collagen fibrils. A, negative staining revealing the periodic striation of the fibrils. B, rotary shadowing showing collagen IX
molecules that decorates the surface of cartilaginous fibrils. C, atomic force microscopy enlightening the microfibrils that composed large fibers (Courtesy of
J.-M. Franc) (printed from Ref. [9] with permission).
Fig. 1. Etude ultrastructurale des fibres de collagŁne. A, coloration n�gative montrant les striations p�riodiques des fibrilles ; B, ombrage tournant montrant les
mol�cules de collagŁne IX d�corant la surface des fibrilles du cartilage ; C, microscopie ą force atomique montrant les mirofibrilles formant les larges fibres
(communiqu� par J.M. Franc) (reproduit de la R�f. [9], avec permission).
2. The fibrillar collagens and their associated collagens:
the FACITs
The fibril-forming or fibrillar collagens represent the first
members of the collagen superfamily to be discovered. They
represent the major products synthesized by connective tis-
sue cells (fibroblasts, osteoblasts and chondrocytes). The
fibrillar collagens comprised five members: the quantita-
tively major fibrillar collagens types I, II and III, and the minor
collagens types V and XI [10]. Because of their relatively
simple structure (a large continuous triple helix flanked by
two terminal globular extensions) and because they represent
the first discovered members of the collagen superfamily,
these former collagens are also called the classical collagens.
They share the unique property to aggregate into highly- Fig. 2. The relative composition and amount of the different collagens
influence the matrix organization of connective tissues. The non oriented
ordered fibrils, which present a banded pattern at the ultra-
thin fibrils present in cartilage are composed of collagen II/XI and IX. Ten-
structural level (Fig. 1). The recent discovery of two addi-
don contains parallel large fibril bundles, which are essentially made of col-
tional novel members, collagens XXIV and XXVII, has
lagen I with small amounts of collagen III and V. Orthogonal array of thin
provided some renewal of interest for this subclass of col-
and regulated fibrils in cornea contains unusual high amounts of collagen V.
lagens. In the late eighties, it becomes clear that fibrils are The heterogenous size of fibrils found in dermis are composed of a mixture
of collagens I and III with small amounts of collagen V.
made with a mixture of major and minor fibrillar collagens
Fig. 2. La composition relative et la proportion des diff�rents collagŁnes
(collagens I, III and V in most connective tissues and col-
influencent l organisation de la matrice des tissus conjonctifs. Les fibres fines,
lagen II and XI in cartilage). The relative composition and
non-orient�es du cartilage sont compos�es des collagŁnes II/XI et IX. Les
amounts of the different collagen types that co-assemble into
tendons contiennent de larges faisceaux fibrillaires ą orientation parallŁle,
heterotypic fibrils govern the structure and organization of compos�s essentiellement de collagŁne I avec de faibles quantit�s de colla-
gŁnes III et V. Les arrangements orthogonaux des fines et r�guliŁres fibrilles
the matrix network and consequently determine the biome-
de la corn�e contiennent une proportion �lev�e de collagŁne V. Les fibres
chanical properties of the tissues (Fig. 2). Soon after, a new
h�t�rogŁnes du derme sont compos�es d un m�lange de collagŁne I et III
subclass of collagens characterized by the interruptions within
avec de faibles quantit�s de collagŁne V.
the triple helix domain was identified and it was shown that
they also interact with fibrils to form more complex alloys 2.1. The fibril-forming collagens
than previously thought. Collagen IX was shown to covalently
interact with collagen II fibrils, whereas collagens XII and The classical fibrillar collagen chains can associate into
XIV were localized at the surface of collagen I/III/V fibrils in homotrimers (collagens II and III), heterotrimers (collagen
skin and tendon, respectively. Based on their common chain XI) or both (collagens I and V) depending on tissue localiza-
structure and their fibril association, the name of FACIT was tion. Collagen V molecular forms are the most heteroge-
given to this subclass of collagens. Recently, this collagen neous among the fibrillar collagens. Besides the heterotrimer
subfamily has expanded to eight members including the novel [a1(V)]2a2(V) found in most tissues, several other different
collagens XVI, XIX, XX, XXI and the most recently reported chain associations exist for collagen V including hybrid mol-
collagen XXII [2] making the FACITs the largest subclass of ecules formed with both collagen V and XI chains [10]. A
the collagen superfamily. novel member of collagen V gene family referred to as a4(V)
S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442 433
was recently described in the rat [11]. There is a near identity the fibrils, could interact with receptors at the cell surface. A
between the rat proa4(V) chain and the human proa3(V) chain number of collagen V receptors have been already identified
but the two chains differ by several features. Whereas the (e.g. [15,16]) but so far they all bind to the collagen V major
a3(V) chain is present in placenta as the heterotrimer triple helix. However, the a4(V) N-propeptide was recently
a1(V)a2(V)a3(V), the a4(V)-containing molecule shows a shown to interact with the heparan sulfate transmembrane pro-
different heterotrimeric chain association [a1(V)]2a4(V). teoglycan syndecan 3, a finding important for its biological
Moreover, proa4(V) chain is solely synthesized by Schwann function. Clearly, much work should be done to elucidate the
cells and its expression is restricted to embryonic and early role of the fribrillar collagen N-propeptides. One possible
postnatal peripheral nerves. The a4(V)-collagen was shown alternative is to approach the function of the N-propeptide by
to display domain-specific effects that regulate peripheral analyzing the role of its subdomains as illustrated by recent
nerves development [12]. work.
Collagen members of a given subclass share a common The CRR domains are present in several copies in two
chain structure. The fibril-forming collagens are all com- homologous proteins the Xenopus chordin and the Droso-
posed of a large continuous triple helix (COL1) bordered by phila sog and bind respectively to bone morphogenetic pro-
the N- and C-terminal extensions called the N- and tein (BMP)-4 and decapentaplegic, both members of the trans-
C-propeptides respectively. The C-propeptide is referred to forming growth factor b (TGF-b) superfamily. The release of
as the NC1 domain, the N-propeptide is divided into sub- these growth factors by xolloid metalloproteinase activity
domains: a short sequence (NC2) that links the major triple establishes a gradient of available morphogens that play a
helix to the minor one (COL2), and a globular N-terminal crucial role in dorsal-ventral patterning. Interestingly, BMP-
end (NC3). Whereas the NC1 domains are well conserved 2 and TGF-b1 were shown to bind to the recombinant trim-
among the fibrillar collagen members, the NC3 domains show eric collagen IIA N-propeptide. This strongly suggests a role
significant variations. They vary in size (from about 200 resi- of the collagen IIA N-propeptide in the regulation of growth
dues to up to 500), in their primary structure and in the com- factor delivery during chondrogenesis [17]. Conversely, mice
position of their subdomains (Fig. 3A). The NC3 domains of that harbored a deletion of the col1a1 exon 2 encoding the
a1(I), a1(IIA), a1(III) and a2(V) chains all harbor a cystein- collagen I CRR-containing domain developed quite nor-
rich repeat domain (CRR) and the a1(V), a3/a4(V), a1(XI), mally [14]. This finding raises questions on the exact role of
a2(XI), a1(XXIV) and a1(XXVII) chains contain a throm- the N-propeptide of collagen I, thought to be involved in vari-
bospondin N-terminal-like (TSPN) domain. It can also be sub- ous collagen biogenesis events (molecular assembly, feed-
jected to alternative splicing as shown for collagens II and XI back regulation of procollagen synthesis and fibrillogenesis).
[13]. The CRRs are characterized by the presence of 10 cys- Little is known about the function of the TSPN domain of the
teine residues in their sequence, which form disulfide bonds fibrillar collagens. The TSPN domain is released during pro-
[14]. The TSPN domain (~200 residues) was first described collagen N-terminal maturation of collagens V and XI but
in the N-terminal domain of the thrompobondin-1 but is fre- the biological relevance of this partial processing has not been
quently encountered in the collagen superfamily members. elucidated yet. However, a spontaneous mutation in human
The fibrillar collagen V, XI, XXIV and XXVII, the FACITs COL5A1 gene that abolished the release of TSPN that nor-
and the multiplexins harbor a TSPN domain in their mally occurred in collagen V maturation, disturbed normal
N-terminal extremities (Fig. 3B). In fibrillar collagens, the fibrillogenesis and caused the classical form of the Elhers
TSPN domain is adjacent to a domain called the variable Danlos syndrome [18]. This finding attests for an important
region (VR). function of this subdomain in fibrillogenesis.
The fibrillar collagens are synthesized as precursors, the With the completion of the genome sequencing, two novel
procollagens, which are secreted in the extracellular space. It members of the fibrillar collagen group, numbered collagens
was commonly admitted that procollagens require pro- XXIV [19] (accession number in TrEMBL database Q7Z5L5)
teolytic removal of the N- and C-terminal propeptides to be and XXVII [20,21] (accession number in TrEMBL database
fully processed into mature and functional molecules. How- Q8IZC6) were identified. Like the classical fibril-forming col-
ever, it turned out that this holds true only for collagens I and lagens, they both contain a long collagenous domain flanked
III. Actually, the NC3 domain can undergo partial proteolytic by globular N- and C- propeptides. Their large amino-
cleavage after procollagen secretion or can be entirely retained terminal domains (up to 550 residues) comprise two subdo-
in the mature molecule as for the proa1(V) and proa2(V) mains, a TSPN domain and a VR as for collagens V and XI
chains respectively. The significance of the persistence of the (Fig. 3A). Their C-propeptides contain eight cysteine resi-
N-propeptide in the mature molecule is still unknown. One dues that make possible homotrimeric association of these
clearly established function of the collagen V and XI collagens. Interestingly, some features of collagens XXIV and
N-propeptides is to contribute to the control of heterotypic XXVII are shared with invertebrate fibrillar collagens [22].
fibril growth by sterically limiting lateral molecule addition The major triple helix is shorter (991 997 amino acids
(see Ref. [10] for review). This flexible domain, that persists depending on the collagen chains and species) and contains
on the mature molecule, emerges at the heterotypic fibril sur- imperfections in the (G X Y)n repeats. Mutations in fibril-
face and thus, unlike the triple helix domain buried within lar collagen genes that generate minor interruptions in the
434 S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442
Fig. 3. Structure of the a chain of fibrillar collagens (A), FACITS (B) (printed from Ref. [9] with permission) and other collagens including membrane
collagens, multiplexins and collagen XXVI (C).
Fig. 3. Structure de la cha�ne alpha des collagŁnes fibrillaires (A), des FACITS (B) (reproduite de la Ref. [9] avec permission) et d autres collagŁnes comprenant
les collagŁnes des membranes, les multiplexines et le collagŁne XXVI (C).
major triple-helical domain are generally disease-causing. and on the lately identified members of this subclass of col-
However, such interruptions can also generate flexible regions lagens.
along the triple helix that favor molecular and cellular inter- Based on conserved structural features that characterize
actions and protease clivage. Human collagen XXVII also the members of this family, five collagens from the last dozen
contains unexpected residues such as tryptophan and cys- identified were recognized as members of the FACIT family:
teine within the triple helix domain. Their significance is (1) the presence of two highly conserved cysteine residues
unclear because they are not all conserved among species and separated by four amino acids at the NC1-COL1 junctions
in the closely related collagen XXIV. Collagen XXIV expres- and (2) the existence of two G X Y triplet imperfections
sion is restricted to bone and cornea both containing hetero- within the COL2 domain (3) a succession of triple-helical
typic fibrils formed with collagens I and V, and it is not found domains connected by short non collagneous domains (4) the
in collagen III-containing tissues such as skin, tendon and presence of a large N-terminal domain that always exhibits a
vessels. Collagen XXVII is strongly expressed in cartilage TSPN subdomain next to the collagenous domain (Fig. 3B).
that contain the heterotypic II/XI fibrils. An interesting issue Besides from these common criteria, the FACITs display
with respect to the reduced length and the interruptions in remarkable divergence in the size and composition of their
their triple helix domain is the question of their capacity to N-terminal domains and in the number of their collagenous
form fibrils or to be incorporated into heterotypic fibrils with domains (from two for collagens type XII, XIV, XX, XXI to
classical fibrillar collagens. 10 for collagen XVI) (Fig. 3B). Whereas TSPN represents
the sole module constituting the N-terminal NC domain of
2.2. The fibrillar associated collagens with interrupted collagens IX, XVI and XIX, in collagens XXI and XXII a
triple helix (FACITs) unique von Willlebrand factor A-like domains (vWA) placed
next to the TSPN domain. In collagens XII, XIV and XX,
The structural aspects of the FACITs have been recently vWA domains alternate with fibronectin type III repeats (FN3)
reviewed [7,9] and more particularly, the cartilaginous col- (Fig. 3B). In addition, in some species, alternative splicing of
lagen IX, which was the first identified member of this sub- collagen XIV, XII and XIX mRNAs occurring in the
class [13]. This review will therefore focus on recent advances N-terminal domains makes the structure and the function of
S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442 435
Fig. 3. (continued)
FACITs again more complex to study at the protein level (see onstrated but interactions mediated by small matrix proteogly-
Ref. [7] for review). The large N-terminal domain of col- cans have been reported [24,25]. Collagen XIV was reported
lagens XII and XIV folds into a trident-like structure as to promote gel contraction [26] and to act as a regulating fac-
observed by rotary shadowing, whereas collagen IX or XIX tor of fibril growth in developing tendon [27]. Collagen XII
N-terminal domains exhibit a single large globular domain expression is up-regulated in wounding caused by excess
(reviewed in [7]). Recent rotary shadowing observations of mechanical stress through intracellular mecanisms that
collagen XIX [23] and XXII [2] molecules show that FAC- involved the FAK-Erk1/2 pathway [28]. Phylogenic analysis
ITs are flexible molecules. showed that collagens XX and XXI [29] are closely related
Although the first FACITs, namely collagens IX, XII, XIV to collagens XII and XIV. However their expression pattern
and XVI, were discovered about 15 years ago, very little is and tissue localization suggest a different role for these two
known about their functions. In absence of strong evidence novel FACITs. Collagen XX (accession number in TrEMBL
for specific role, the FACITs were generally proposed to be database Q90ZA0) is localized to corneal epithelium, a pat-
involved in the stabilization and integrity of the extracellular tern similar to that of collagen XII [30]. Collagen XXI (acces-
matrices. However, most FACIT members present restricted sion number in TrEMBL database Q96P44) is highly ex-
and developmentally regulated expression patterns suggest- pressed at fetal stages [31]. It is present in different developing
ing that they can ensure more specific and important func- connective tissues but it is particularly abundant in vascular
tions than previously reported. Generation of null mutation walls [32]. Its expression in smooth muscle cells is stimu-
in collagen genes has proven helpful for elucidating collagen lated by platelet-derived growth factor, indicating that col-
function. It is most certain, as recently shown for collagen lagen XXI might participate to the elaboration of the vascu-
XIX (see below), that gene targeting technology will also be lar matrix network [31]. Finally, the recently reported collagen
important in the future to approach FACIT functions. XXII (accession number in TrEMBL database Q8NFW1) was
Contrary to collagen IX, no covalent cross-linking between presented as a novel marker of tissue junction because of its
collagens XII and XIV and fibrillar collagens has been dem- unique tissue distribution [2]. As shown for collagen XVI,
436 S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442
Fig. 3. (continued)
collagen XXII might interact with components of microfibrils tains 19 repeats of G X Y, co-localizes with cytoskeletal
rather than with collagen fibrils. Collagen XVI was found to structures at lateral and apical surfaces of cells [39] and is
be associated to cartilage heterotypic II/IX/XI fibrils, an involved in the signaling pathway required for epithelial mor-
expected localization for the FACITs [23], but it co-localized phogenesis [86]. The scavenger receptors type A (SR-AI and
with fibrillin-1 filaments in papillary dermis [33]. Collagen SR-AII) and MARCO are classical scavenger type receptors
XVI is supposed to play an important role in stabilizing fibro- with collagen-like domains, which mediate both ligand inter-
blasts in dermal matrix. From a structural point of view, col- nalization and cell adhesion and participate in lipid metabo-
lagen XIX is closely related to collagen XVI. Initially iso- lism [40]. MARCO plays a role in the anti-bacterial host
defense as does membrane-type collectin from placenta (col-
lated from a human rhabdomyosarcoma cell line [34],
lectin placenta-1), which differs from other collectins in being
collagen XIX is basically expressed in epithelial basement
a type II membrane protein [41] and resembles type A scav-
membrane zones [35]. Its strong expression in differentiating
enger receptors.
muscle cells suggests that collagen XIX is involved in initial
Collagens XIII, XVII, XXIII and XXV are type II trans-
stages of skeletal muscle cell differentiation [36]. Along this
membrane proteins with the N-terminus located inside the
line, mice harboring null and structural mutations on
cell, a single pass hydrophobic transmembrane domain and
Col19a1 gene provide further evidence that collagen XIX is
several extracellular collagenous domains (Fig. 3C). The fold-
crucial for muscle physiology and differentiation. Notably,
ing of the triple helix in the ectodomain of collagens XIII
the phenotype includes a failure in esophageal muscle trans-
[42] and XVII [43] proceeds from the N- to the C-terminus,
differentiation [37].
in opposite orientation to that of the fibrillar collagens. Col-
lagens XIII, XXIII and XXV, MARCO and ectodysplasin-
3. Membrane collagens and collagen-like membrane A1 contain two separate coiled-coil motifs, which may func-
proteins tion as independent oligomerization domains [42,44,45]. The
NC4 C-terminal noncollagenous domain (20 amino acids) of
This sub-group is comprised of homotrimeric collagens collagens XIII, XXIII and XXV shows significant identity
XIII, XVII, XXIII, XVII and of collagen-like membrane pro- and is thought to be involved in functional interaction with
teins such as ectodysplasin, macrophage receptor with col- cell surface or extracellular matrix proteins [3].
lagenous structure (MARCO) and macrophage scavenger Collagen XIII is the first member of the collagen family,
receptors [38], which have not been referred to as collagens which has been characterized as a membrane protein. It is a
so far. Ectodysplasin, the extracellular domain of which con- component of epidermal cell-matrix and cell cell contacts in
S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442 437
cultured keratinocytes [46]. Collagen XVII, also referred to XXV/CLAC-P specifically bind to fibrillized Ab, which sug-
as bullous pemphigoid antigen 180 or BP180, is also a kera- gests that both forms are involved in b-amyloidogenesis and
tinocyte transmembrane protein [47]. Collagen XXIII, which neuronal degeneration in Alzheimer s disease [4]. The Alzhe-
has been identified in metastatic tumor cells and in normal imer s disease amyloid-associated protein called AMY was
heart, is expressed at the surface of a rat prostate carcinoma found to be identical to CLAC ( [4] and references therein).
cell line,AT2.1 cells [3]. Collagen XXV/Collagen-LikeAlzhe- A membrane collagen-like molecule, the scavenger receptor
imer amyloid plaque Component Precursor (CLAC-P) is also type A, has also been shown to bind to the fibrillized form of
expressed at the surface of HEK 293 stably transfected cells Ab and to contribute to its scavenging by microglial cells
[4]. ( [4], references therein).
Membrane collagenous proteins function both as cell sur-
face receptors and as soluble extracellular molecules because
their ectodomains are released from the cell surface by shed- 4. Multiplexins (multiple triple helix domains
ding. The extracellular domain of membrane collagens, which and interruptions)
contains triple-helical domains, is of variable length. It is made
of three collagenous domains in collagen XIII [48], XXIII Collagens XV and XVIII are homotrimers with strong
[3] and XXV [4] and of 15 domains in collagen XVII [47]. sequence and structural homologies in the C-terminal part of
The ectodomain of collagen XIII undergoes alternative splic- the molecule. They contain multiple triple-helical domains
ing, which affects triple-helical (COL1 and COL3) and non (nine for collagen XV and 10 for collagen XVIII) and a
triple-helical domains [48]. Four alternatively spliced iso- N-terminal thrombospondin-1 domain similar to the N-termi-
forms of collagen XXV, leading to variability in length of its nal heparin-binding domain of thrombospondin-1, which is
extracellular domain, have been reported [4]. also present in some fibrillar collagens and in FACITs as
Ectodomain cleavage at a furin-like site has been observed described above (Fig. 3C). C-terminal heptad repeats have
for collagen XIII [42], XVII [49], XXIII [3], XXV [4] and been found in the oligomerization domains of the multiplex-
ectodysplasin [50]. Shed ectodomains of membrane col- ins [45]. Multiplexins carry glycosaminoglycan chains, chon-
lagens bind to other components of extracellular matrix, such droitin sulfate for collagen XV and heparan sulfate chains for
as fibronectin, nidogen-2 and perlecan for collagen XIII [51], collagen XVIII [59,60] and are thus considered not only as
heparin for collagens XIII [51] and XXIII [3] and to integrin collagens, but also as proteoglycans.
receptors. Collagen XIII binds to a1b1 integrin [51], col- The C-terminal domains of these two collagens are strongly
lagen XVII to a5b1 and avb1 integrins [52,53], whereas col- homologous and contain fragments, endostatin-XVIII and
lagen XXIII may contribute to cell adhesion via its RGD site endostatin-XV (called restin for related to endostatin)
and its three KGD motifs [3]. The release of the ectodomain (Fig. 3C), which are released from the parent molecule by
of collagen XVII from the cell surface is associated with proteolysis and share 61% of identity in their primary
altered keratinocyte motility in vitro [49], and COL15, the sequence. These two proteolytic fragments belong to a new
largest collagenous domain of collagen XVII, promotes adhe- class of molecules collectively referred to as matricryptins
sion of epithelial cells and fibroblasts [54]. It is thus likely [61]. These fragments (~18 30 kDa) are derived, among other
that the shed domains of membrane collagens contribute to extracellular sources, from the C-terminal domain of col-
the regulation of cell behavior. lagens type IV, VIII, XV and XVIII, which are associated to
Collagen XIII is concentrated in the focal adhesions and is basement membranes. The NC1 domains of a1(IV), a2(IV),
also found in a range of adherens junctions in cultured skin a3(IV) and a1(VIII) chains give rise to fragments called,
fibroblasts [55] as well as in other cell types [56]. Collagen respectively arresten, canstatin, tumstatin and vastatin
XXV, which is deposited in brain, may play a role in adher- [62 64]. These matricryptins modulate endothelial cell pro-
ens junction between neurons [4]. Collagen XIII is involved liferation and migration, induce endothelial cell apoptosis,
in the adhesion of cells to basement membranes [71] and in inhibit angiogenesis and tumor growth [62 64] and interact
the linkage between muscle fiber and basement membrane with cell surface via integrins. avb3 and avb5 integrins bind
[57]. It also has an important role in certain adhesive interac- to the NC1 domain of the a3(IV)chain and to endostatin,
tions that are necessary for normal development [56]. Col- whereas the a5b1 integrin interacts with endostatin alone.
lagen XVII is a major component of hemidesmosome, where Human endostatin was found by X-ray crystallography to con-
it interacts with hemidesmosomal components BP230, plec- tain a zinc binding site, which is located at the N-terminus
tin and the integrin a6b4 [47]. [65], and seems to be required for endostatin interaction with
Collagen XIII, which enhances neurite outgrowth [58], and heparin/heparan sulfate [66].
collagen XXV are expressed by neurons, collagen XXV/ Collagens XV and XVIII occur in the epithelial and endot-
CLAC-P being specifically expressed by this cell type and helial basement membrane zones of a wide variety of tissues
not in astrocytes, microglia or meningeal fibroblasts [4]. The [67], but despite their structural homologies, double knock-
extracellular CLAC domain of membrane collagen XXV is out mice reveal a lack of major functional compensation
massively deposited within extracellular b amyloid plaques. between them [68]. Their biological roles are essentially sepa-
Both secreted and membrane-anchored forms of collagen rate, that of collagen XV in the muscle and that of collagen
438 S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442
XVIII in the eye [68]. Lack of type XV collagen in mice in, but not restricted to, testis and ovary during the develop-
results in mild skeletal myopathy and increases vulnerability ment. It is difficult to classify this collagen within the col-
to exercise-induced skeletal muscle and cardiac injury. Col- lagen superfamily, because it lacks extensive structural simi-
lagen XV appears to function as a structural component larities with existing sub-families. It does not appear to be a
needed to stabilize skeletal muscle cells and microvessels [69] fibrillar collagen because it contains two major collagenous
and might be a tumor suppressor [70]. domains (Fig. 3C) and the disulfide bonds that form trimers
Collagen XVIII plays a critical role in the development of collagen XXVI are located in the N-terminal NC domain
and function of the eye, specially for normal induction of [5], whereas in fibrillar collagens the three a chains are
blood vessel formation and for anchoring vitreal collagen disulfide - bonded in the C-propeptide region. It does not con-
fibrils to the inner limiting membrane [71]. Furthermore, tain either the conserved motif characterized by the presence
mutations in COL18A1 gene lead to Knobloch syndrome, an of two cysteine residues at the COL1-NC1 junction or a TSPN
autosomal recessive disorder characterized by the occur- domain found in FACITs. Collagen XXVI possesses two
rence of vitreoretinal degeneration with retinal detachment, coiled-coil oligomerization domains found in membrane col-
high myopia, macular abnormalities and occipital encepha- lagens XIII, XXIII and XXV [44,45], but does not contain a
locele. The frameshift mutations are located in different transmembrane sequence. Furthermore, its ectodomain is not
regions of the COL18A1 gene [72]. cleaved by furin convertase as described above for mem-
One of the physiological roles of collagen XVIII might be brane collagens despite the presence of a consensus furin pro-
to maintain the structural integrity of basement membranes. tease cleavage site [5].
Its C-terminal fragment, endostatin, is often co-localized with According to analysis of the following genes (EMID2 or
perlecan, which could connect collagen XVIII to basement EMU2 and COL26A1), the collagen a1(XXVI) chain is iden-
membrane via the binding of its endorepellin C-terminal tical to the EMI domain containing protein 2, also called emi-
domain to endostatin [73,74]. The role of collagen XVIII in lin and multimerin (Emu)-domain containing protein 2 or
basement membrane assembly is further supported by the Emu2 protein (Q96A83 entry in Swiss Prot database for the
binding of endostatin to other components of basement mem- human protein EMD2_HUMAN, http://www.us.expasy.org/
branes, namely heparan sulfate, laminin-1 fibulin-1 and fibu- cgi-bin/niceprot.pl). Emu2 belongs to the Emu family, all the
lin-2 and nidogen-2 [75 77]. members of which share an N-terminal cysteine-rich domain
Collagen XVIII also plays a role in organogenesis, where (EMI domain). Four of these proteins, emilins1 and 2 (Elas-
it participates in epithelial branching morphogenesis in the tin Microfibril Interface Located proteINs) and Emu1 and 2
lung and the kidney [78] and in various developmental pro- (Emu-domain containing proteins), contain at least a collag-
cesses through the Wnt signaling pathway triggered by its enous domain, and are secreted and deposited in the extracel-
N-terminal frizzled domain [79]. Indeed, the longest lular matrix [82]. Emu1 and Emu2 show a similar structural
N-terminal collagen XVIII variant contains a cysteine-rich organization with a N-terminal signal peptide followed by a
region homologous to the extracellular domain of frizzled EMI domain, two collagen stretches and a conserved
receptors, which binds the Wnt signaling molecules. Col- C-terminal domain of unknown function. These two proteins
lagen XVIII might participate in neurogenesis. It is associ- are able to form homo- and hetero-trimers via disulfide bond-
ated with axons, enriched near synaptic contacts and partici- ing within their EMI domains [85]. This opens the possibility
pates in synapse organization via its C-terminal NC1 domain for collagen XXVI to be an heterotrimer because it is identi-
[80]. The NC1/endostatin domain regulates cell migration and cal to Emu2, which forms heterotrimeric complex with the
axone guidance in Caenorhabditis elegans [81]. Further- Emu1 protein. Whether Emu1 protein can be considered as
more, collagen XVIII is expressed in human brain and is another a chain of collagen XXVI remains to be ascertained.
deposited in senile plaques in patients with Alzheimer s dis- Emu1 and Emu2 might be incorporated into collagen fibers
ease [82]. Its C-terminal fragment, endostatin, is also associ- as macromolecular connectors, similar to FACITs, with the
ated with neuronal and paracellular deposits in brain of EMI and the C-terminal domains available for further inter-
patients with Alzheimer s disease [83], has the propensity to actions [85].
form cross-b-structure and to aggregate into amyloid depos- Emilins 1 and 2 are associated with elastic fibers at the
its. Amyloid fibrils formed by endostatin are cytotoxic to interface between amorphous elastin and microfibrils [86].
murine neuroblastoma cells and to endothelial cells [84]. The collagenous domain of emilin1 comprises 17 uninter-
rupted G X Y triplets and is able to form a triple helix, while
it is unlikely that the interrupted seventeen triplets of emilin
5. Collagen XXVI and the Emu family (emilin 2 can trimerize.
and multimerin)
The a1(XXVI) collagen chain has been discovered by yeast 6. Other collagen-like molecules
two-hybrid screening of a 17.5 whole mouse embryo cDNA
library using the collagen-specific molecular chaperone heat Type II membrane collagen-like molecules and members
shock protein 47 as a bait [5]. Collagen XXVI is expressed of the Emu family containing a collagenous domain have been
S. Ricard-Blum, F. Ruggiero / Pathologie Biologie 53 (2005) 430 442 439
discussed above with membrane collagens and collagen XXVI 8. Conclusion
respectively. The other molecules containing a collagenous
domain are presented below. Although some of them are The sequencing of the human genome being completed, it
sometimes referred to as collagens, they are not assigned a is likely that most, if not all the members, of the collagen
Roman number. superfamily are now known. This will be a good point to try
to clarify the criteria used to name a protein a collagen. Some
Several proteins contain both a triple-helical domain and a
members of the emu family will be likely candidates to be
C-terminal globular domain similar to that found in the
classified as collagens. It would be also interesting to deter-
complement component C1q (see Ref. [7 9] for reviews,
mine if, as currently admitted, all the a collagen chains
[87]): C1q, chipmunk hibernation-related proteins, an inner
recently discovered, and particularly a1(XXVI) as discussed
ear-specific structural protein also referred to as saccular col-
above, exist really as homotrimers in tissues.
lagen, the adipocyte-derived hormone adiponectin, C1q-
Another field of major interest for future investigations con-
related factor which is not secreted but expressed exclusively
cerns gene therapy to treat collagen-related diseases. A high
in cytoplasm and a novel short-chain collagen called comple-
number of mutations have been reported in collagen genes
ment C1q tumor necrosis factor-related protein 5 ( [87] and
leading to genetic disorders [7,8]. Although numerous experi-
references therein).
mental studies have been performed to correct genetic defects
Other collagen-like molecules include collectins and
in several collagen-related diseases, gene-based therapy pres-
ficolins, the humoral lectins of the innate immune defense.
ently remains in the early stages of preclinical research. Suc-
They possess a collagenous region and a carbohydrate recog-
cessfull attempts have been made to restore normal expres-
nition domain, which is a C-type lectin domain in collectins
sion of products of mutated genes in osteogenesis imperfecta,
and a fibrinogen-like domain in ficolins [41]. There are four
a syndrome of congenital brittle bones secondary to muta-
groups of collectins: the mannan-binding protein group, the
tions in the COL1A1 and COL1A2 genes [92], Alport syn-
surfactant protein A group, the surfactant protein D group,
drome, a progressive inherited nephropathy associated with
collectin liver 1 and a membrane-type collectin, collectin pla-
mutation in COL4A3, COL4A4, or COL4A5 genes [93], and
centa 1, and three human ficolins (L-, M- and H-ficolins).
epidermolysis bullosa, a family of inherited blistering skin
These proteins are sometimes referred to as defense col-
diseases with variable clinical phenotypes caused by muta-
lagens, together with complement C1q and adiponectin [38].
tions in the COL7A1 gene and in the COL17A1 gene [94].
Membrane-bound defense collagens correspond to the type
A macrophage scavenger receptors and MARCO [38].
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