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The Collagen Family

Sylvie Ricard-Blum

Institut de Biologie et Chimie des Prote´ines, UMR 5086 CNRS, Universite´ Lyon 1, Lyon, 69367, France Correspondence: [email protected]

Collagens are the most abundant proteins in mammals. The collagen family comprises 28 members that contain at least one triple-helical domain. Collagens are deposited in the extra- cellular matrix where most of them form supramolecular assemblies. Four collagens are type II membrane proteins that also exist in a soluble form released from the cell surface by shed- ding. Collagens play structural roles and contribute to mechanical properties, organization, and shape of tissues. They interact with cells via several receptor families and regulate their proliferation, migration, and differentiation. Some collagens have a restricted tissue distri- bution and hence specific biological functions.

ollagens are the most abundant proteins in collagen has been called collagen XXIX (So¨der- Cmammals (30% of total protein mass). ha¨ll et al. 2007), but the COL29A1 gene was Since the discovery of collagen II by Miller and shown to be identical to the COL6A5 gene, and Matukas (1969), 26 new collagen types have been the a1(XXIX) chain corresponds to the a5(VI) found, and their discovery has been accelerated chain (Gara et al. 2008). The common structur- by molecular biology and gene cloning. Several al feature of collagens is the presence of a tri- reviews on the collagen family have been pub- ple helix that can range from most of their lished (Miller and Gay 1982; van der Rest and Gar- structure (96% for collagen I) to less than 10% rone 1991; Kadler 1995; Ricard-Blum et al. 2000, (collagen XII). As described in the following dis- 2005; Myllyharju and Kivirikko 2004; Ricard- cussion, the diversity of the collagen family is Blum and Ruggiero 2005; Kadler et al. 2007; Gor- further increased by the existence of several a don and Hahn 2010) and even if the question chains, several molecular isoforms and supra- “What is collagen, what is not?” (Gay and Miller molecular structures for a single collagen type, 1983) may still be valid, numerous answers have and the use of alternative promoters and alter- been provided giving new insights into the struc- native splicing. ture and the biological roles of collagens. The criteria to name a protein collagen are not well defined and other proteins containing one triple-helical domain (Table 2) are not THE COLLAGEN SUPERFAMILY numbered with a Roman numeral so far and do The collagen superfamily comprises 28 mem- not belong to the collagen family sensu stricto. bers numbered with Roman numerals in verte- Some of them, containing a recognition domain brates (I–XXVIII) (Table 1). A novel epidermal contiguous with a collagen-like triple-helical

Editors: Richard Hynes and Kenneth Yamada Additional Perspectives on Extracellular Matrix Biology available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004978 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004978

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S. Ricard-Blum

Table 1. The collagen family. Collagen type a Chains Molecular species

Collagen I a1(I), a2(I) [a1(I)]2, a2(I) [a1(I)]3 Collagen II a1(II) [a1(II)]3 Collagen III a1(III) [a1(III)]3 Collagen IV a1(IV), a2(IV), a3(IV), a4(IV), [a1(IV)]2, a2(IV) a5(IV), a6(IV) a3(IV), a4(IV), a5(IV) [a5(IV)]2, a6(IV) a Collagen V a1(V), a2(V), a3(V), a4(V) [a1(V)]2, a2(V) [a1(V)]3 [a1(V)]2a4(V) a1(XI)a1(V)a3(XI) Collagen VI a1(VI), a2(VI), a3(VI), a4(VI)b, a5(VI)c, a6(V) Collagen VII a1(VII) [a1(VII)]3 Collagen VIII a1(VIII) [a1(VIII)]2, a2(VIII) a1(VIII), [a2(VIII)]2 [a1(VIII)]3 [a2(VIII)]3 Collagen IXe a1(IX), a2(IX), a3(IX) [a1(IX), a2(IX), a3(IX)] Collagen X a1(X) [a1(X)]3 Collagen XI a1(XI), a2(XI), a3(XI)d a1(XI)a2(XI)a3(XI) a1(XI)a1(V)a3(XI) e Collagen XII a1(XII) [a1(XII)]3 Collagen XIII a1(XIII) [a1(XIII)]3 e Collagen XIV a1(XIV) [a1(XIV)]3 Collagen XV a1(XV) [a1(XV)]3 e Collagen XVI a1(XVI) [a1(XVI)]3 Collagen XVII a1(XVII) [a1(XVII)]3 Collagen XVIII a1(XVIII) [a1(XVIII)]3 e Collagen XIX a1(XIX) [a1(XIX)]3 e Collagen XX a1(XX) [a1(XX)]3 e Collagen XXI a1(XXI) [a1(XXI)]3 e Collagen XXII a1(XXII) [a1(XXII)]3 Collagen XXIII a1(XXIII) [a1(XXIII)]3 Collagen XXIV a1(XXIV) [a1(XXIV)]3 Collagen XXV a1(XXV) [a1(XXV)]3 Collagen XXVI a1(XXVI) [a1(XXVI)]3 Collagen XXVII a1(XXVII) [a1(XXVII)]3 Collagen XXVIII a1(XXVIII) [a1(XXVIII)]3 Individual a chains, molecular species, and supramolecular assemblies of collagen types. aThe a4(V) chain is solely synthesized by Schwann cells. bThe a4(VI) chain does not exist in humans. cThe a5(VI) has been designated as a1(XXIX). dThe a3(XI) chain has the same sequence as the a1(II) chain but differs in its posttranslational processing and cross-linking. eFACIT, Fibril-Associated Collagens with Interrupted Triple helices.

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Collagens

Table 2. Proteins containing a collagen-like domain. Protein name Domain composition Cellular component Complement C1q (subcomponent Collagen-like domain Secreted subunits A, B, C) C1q domain Adiponectin Collagen-like domain Secreted C1q domain Mannose-binding protein C Collagen-like domain Secreted C-type lectin Cystein-rich domain Ficolins 1, 2, and 3 Collagen-like domain Secreted Fibrinogen-like domain Acetylcholinesterase collagenic tail Collagen-like domain Secreted peptide (collagen Q) Proline-rich attachment domain domain Pulmonary surfactant-associated Collagen-like domain Secreted proteins A1 and A2 C-type lectin Extracellular matrix Pulmonary surfactant-associated Collagen-like domain Secreted protein D C-type lectin Extracellular matrix Ectodysplasin A Collagen-like domain Single-pass type II membrane protein Signal-anchor for type II membrane protein Cytoplasmic Macrophage receptor (MARCO) SRCR Single-pass type II membrane protein Collagen-like domain Signal-anchor for type II membrane protein Cytoplasmic Gliomedin Pro-rich domain Single-pass type II membrane protein Olfactomedin-like domain Collagen-like domain Signal-anchor for type II membrane protein EMI domain-containing protein 1 EMI domain Secreted Collagen-like domain Extracellular matrix Emilin-1 EMI domain Secreted Collagen-like domain Extracellular matrix C1q domain Emilin-2 EMI domain Secreted Collagen-like domain Extracellular matrix C1q domain The names are those indicated for human proteins in the UniProtKB database (http://www.uniprot.org/, release 2010_08 - Jul 13, 2010).

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S. Ricard-Blum

domain, are called soluble defense collagens exist in two different forms, a transmembrane (Fraser and Tenner 2008), and gliomedin is rec- form and a soluble one, released by shedding, ognized as a membrane collagen (Maertens et al. that regulates cell behavior (Franzke et al. 2005). 2007).

THE STRUCTURAL ORGANIZATION Beyond Collagen Types: Increased OF COLLAGENS Molecular Diversity of the Collagen Family A Common Structural Motif: Collagens consist of three polypeptide chains, The Triple Helix called a chains, numbered with Arabic numer- als. Beyond the existence of 28 collagen types, Collagen a chains vary in size from 662 up to further diversity occurs in the collagen family 3152 amino acids for the human a1(X) and because of the existence of several molecular a3(VI) chains respectively (Ricard-Blum et al. isoforms for the same collagen type (e.g., colla- 2000; Gordon and Hahn 2010). The three a gens IV and VI) and of hybrid isoforms com- chains can be either identical to form homo- prised of a chains belonging to two different trimers (e.g., collagen II) (Table 1) or different collagen types (type V/XI molecules) (Table 1). to form heterotrimers (e.g., collagen IX) (Table Indeed collagen XI is comprised of three a 1). The three a chains of fibril-forming colla- chains assembled into a heterotrimer (Table 1), gens are three left-handed polyproline II helices but the a(XI) chain forms type V/XI hybrid twisted in a right-handed triple helix with a collagen molecules by assembling with the one-residue stagger between adjacent a chains. a1(V) chain in vitreous (Mayne et al. 1993) The triple helix is stabilized by the presence and cartilage (Wu et al. 2009) (Table 1). There of glycine as every third residue, a high content is an increase in a1(V) and a decrease in of proline and hydroxyproline, interchain hy- a2(XI) during postnatal maturation of cartilage drogen bonds, and electrostatic interactions (Wu et al. 2009). (Persikov et al. 2005), involving lysine and as- The use of two alternative promoters gives partate (Fallas et al. 2009). The triple-helical different forms of a1(IX) and a(XVIII) chains, sequences are comprised of Gly-X-Y repeats, X and alternative splicing contributes to the exis- and Y being frequently proline and 4-hydroxy- tence of several isoforms of a1(II), a2(VI), proline, respectively. Location of 3-hydroxy- a3(VI), a1(VII), a1(XII), a1(XIII), a1(XIV), proline residues, which could participate in a1(XIX), a1(XXV), and a1(XXVIII) chains. the formation of supramolecular assemblies, Splicing events are sometimes specific to a tissue have been identified in collagens I, II, III, and and/or a developmental stage, and splicing V/XI (Weiss et al. 2010). The triple helix is rod- variants modulate collagen functions. Several shaped, but it can be flexible because of the collagens (IX, XII, XIV, XV, XVIII) carry glyco- presence of Gly-X-Y imperfections (one to three saminoglycan chains (chondroitin sulfate and/ amino acid residues) and interruptions (up to or heparan sulfate chains) and are considered 21–26 interruptions in the collagen IV chains, also as proteoglycans. Khoshnoodi et al. 2008). These interruptions Additional levels of functional diversity are are associated at the molecular level with local due (1) to the proteolytic cleavage of several col- regions of considerable plasticity and flexibility lagen types to release bioactive fragments dis- and molecular recognition (Bella et al. 2006). playing biological activities of their own, and (2) to the exposure of functional cryptic sites Collagens are Multidomain Proteins because of conformational changes induced in collagens by interactions with extracellular pro- Fibrillar collagens contain one major triple-hel- teins or glycosaminoglycans, multimerization, ical domain. In contrast, collagens belonging to denaturation, or mechanical forces (Ricard- the fibril-associated collagens with interrupted Blum and Ballut 2011). Membrane collagens triple-helices (FACIT), the multiplexins and

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Collagens

the membrane collagen subfamilies contain sev- domains (Shaw and Olsen 1991) and that colla- eral triple-helical domains (Fig. 1). The discov- gens were multidomain proteins (Fig. 1). The ery of collagen IX, the first FACIT, was a major non-collagenous domains participate in struc- breakthrough in the collagen field showing tural assembly and confer biological activities that triple-helical, collagenous domains could to collagens. They are frequently repeated with- be interspersed among non-collagenous (NC) in the same collagen molecule and are also

Fibril-forming collagens

α1 (I) C

α2 (I)

α1 (II) C

α 1 (III) C

α1 (V) TSP

α 2 (V) C

α3 (V) TSP

α1 (XI) TSP

α2 (XI) TSP

α1 (XXIV) TSP

α1 (XXVII) TSP

Fibril-associated collagens with interrupted triple helices

α1 (IX) TSP

α2 (IX)

α3 (IX)

α1 (XII) TSP

α1 (XIV) TSP

α1 (XVI) TSP

α1 (XIX) TSP

α1 (XX) TSP

α1 (XXI) TSP

α1 (XXII) TSP

Non-collagenous domain Fibronectin type III repeat C Alternatively-spliced region

Triple-helical domain (Gly-X-Y) TSP Thrombospondin domain

von Willebrand factor A domain C-terminal propeptide

Figure 1. Structural organization of collagens. Domain composition and supramolecular assemblies of colla- gens. COL, Collagenous, triple-helical, domains; NC, Non-collagenous, nontriple-helical, domains. They are numbered from the carboxy- to the amino-terminus, except for collagen VII. (Figure continued on following page.)

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S. Ricard-Blum

Network-forming collagens

α1 and α2 (IV)

α3, α4, α5, and α6 (IV)

= 200 aa α1 (VIII)

α2 (VIII)

α1 (X)

= 200 aa

Collagens VI, VII, XXVI, and XXVIII

α1 (VI)

α2 (VI)

α3 (VI)

α4 (VI)

α5 (VI)

α6 (VI)

α1 (VII)

α1 (XXVIII)

= 200 aa

α1 (XXVI)

= 200 aa Membrane collagens Intracellular Extracellular α1 (XIII)

α1 (XVII)

α1 (XXIII)

α1 (XXV)

= 200 aa Multiplexins (collagens XV and XVIII)

α1 (XV) TSP

α1 (XVIII) TSP

= 200 aa

Non-collagenous domain Triple-helical domain (Gly-X-Y) Membrane domain

von Willebrand factor A domain Fibronectin type III repeat Kunitz domain

TSP Thrombospondin domain C1q domain EMI domain

Figure 1. Continued.

found in other extracellular proteins. Fibronec- XXII, and XXVIII (Fig. 1). The role of the Kunitz tin III, Kunitz, thrombospondin-1, and von domain that is cleaved during the maturation Willebrand domains are the most abundant in of collagens VI or VII is not yet elucidated. collagens (Fig. 1). The von Willebrand domain Collagen XXVIII closely resembles collagen VI that participates in protein-protein interactions by having a triple-helical domain flanked by is found in collagens VI, VII, XII, XIV,XX, XXI, von Willebrand domains at the amino-terminus

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Collagens

and a Kunitz domain at the carboxy-terminus, recognition and trimeric assembly (Khosh- but its tissue distribution is more restricted noodi et al. 2006). thancollagenVI(Veit et al.2006).The fourmem- brane collagens (Table 1) are single-pass type II SUPRAMOLECULAR ASSEMBLIES OF membrane proteins comprising a cytoplasmic COLLAGENS domain, a transmembrane domain, and several triple-helical domains located in the extracellu- When visualized by electron microscopy after lar matrix (Franzke et al. 2005). rotary shadowing, collagen molecules are vi- sualized as rods varying in length from approx- imately 75 nm for collagen XII to 425 nm for The Trimerization Domains collagen VII (Ricard-Blum et al. 2000). The mo- Folding of the triple helix requires trimerization lecular structure of collagen XV extracted from domains that ensure the proper selection and tissue has an unusual shape, most molecules alignment of collagen a chains, and allows being found in a knot/figure-of-eight/pretzel the triple helix to fold in a zipper-like fashion configuration (Myers et al. 2007), although (Khosnoodi et al. 2006). The formation of the recombinant collagen XV appears elongated in triple-helix is initiated from the carboxyl termi- rotary shadowing (Hurskainen et al. 2010). nus for fibrillar collagens and from the amino Kinks caused by the presence of non-collage- terminus for membrane collagens (Khosnoodi nous domains are observed in electron mi- et al. 2006). The trimerization domains of colla- croscopy of nonfibrillar collagen preparations. gens IV,VIII, and X that assemble into networks Non-collagenous domains can also be charac- are their non-collagenous carboxy-terminal terized by electron microscopy after rotary domains. The carboxy-terminal trimeric NC1 shadowing (e.g., the trimeric carboxy-terminal domains of the homotrimers [a1(VIII)]3 and NC1 domain of collagen XVIII, Sasaki et al. [a1(X)]3 are comprised of a ten-stranded b [1998]). sandwich, and expose three strips of aro- matic residues that seem to participate in their Fibril-Forming Collagens supramolecular assembly (Bogin et al. 2002, Kvansakul et al. 2003) (PDB ID: 1O91). The tri- Collagens can be subdivided into subfamilies merization domain of collagen XVIII, a mem- based on their supramolecular assemblies: fi- ber of the multiplexin subfamily, spans the brils, beaded filaments, anchoring fibrils, and first 54 residues of the non-collagenous car- networks (Fig. 2). Most collagen fibrils are com- boxy-terminal (NC1) domain. Each chain has prised of several collagen types and are called four b-strands, one a-helix, and a short 310 heterotypic. Collagen fibrils are made of colla- helix (Boudko et al. 2009) (PDB ID: 3HON gens II, XI, and IX or of collagens II and III and 3HSH). This domain is smaller than the (Wu et al. 2010) in cartilage, of collagens I trimerization domain of fibrillar collagens and III in skin, and of collagens I and V in cor- (250 residues) and shows high trimeriza- nea (Bruckner et al. 2010). Furthermore, colla- tion potential at picomolar concentrations gen fibrils can be considered as macromolecular (Boudko et al. 2009). The trimerization domain alloys of collagens and non-collagenous pro- of collagen XV, the other multiplexin, has been teins or proteoglycans. Indeed, small leucine- modeled by homology. The trimerization of rich proteoglycans regulate fibrillogenesis, as collagens IX and XIX (FACITs) is governed by do collagens V and XIV (Wenstrup et al. 2004; their NC2 domain (Fig. 1), the second non- Ansorge et al. 2009), and could also influence collagenous domain starting from the car- collagen cross-linking (Kalamajski and Oldberg boxyl terminus (Boudko et al. 2008, Boudko 2010). Fibronectin and integrins could act as et al. 2010). The C1 subdomain located at the organizers, and collagens Vand XI as nucleators carboxyl terminus of a1, a2 and a3 chains of for fibrillogenesis of collagens I and II (Kadler collagen VI is sufficient to promote chain et al. 2008). Collagen fibrillogenesis has been

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S. Ricard-Blum

Fibrils Hexagonal networks (collagens VIII and X)

FACITs (collagen IX)

TSP

Beaded filaments (collagen VI)

Network (collagen IV)

Anchoring fibrils (collagen VII)

Non-collagenous domain

Triple-helical domain (Gly-X-Y) TSP Thrombospondin domain

Figure 2. Supramolecular assemblies formed by collagens.

extensively studied in tendons, but the site of (Orgel et al. 2006). In contrast, cartilage fibrils the initial steps of fibrillogenesis is not clearly are made of a core of four microfibrils (two of defined so far. They may take place in extra- collagen II and two of collagen XI) surrounded cellular compartments where fibril interme- by a ring of ten microfibrils, each microfibril diates are assembled and mature fibrils grow containing five collagen molecules in cross- through a fusion process of intermediates section (Holmes and Kadler 2006). (Zhang et al. 2005), or they may occur intra- cellularly, in Golgi-to-membrane carriers con- Fibril-Associated Collagens taining 28-nm-diameter fibrils that are targeted to plasma membrane protrusions called fibri- The FACITs do not form fibrils by themselves, positors (Canty et al. 2004). The two models but they are associated to the surface of collagen have been discussed (Banos et al. 2008). fibrils. Collagen IX is covalently linked to the Collagen fibrils show a banding pattern surface of cartilage collagen fibrils mostly com- with a periodicity (D) of 64–67 nm (Bru¨ckner posed of collagen II (Olsen 1997), and collagens 2010), and collagen molecules are D-staggered XII and XIV are associated to collagen I-con- within the fibrils. Collagen fibrils range in diam- taining fibrils. Collagen XV is associated with eter from approximately 15 nm up to 500 nm or collagen fibrils in very close proximity to the more depending on the tissue (Kadleret al. 2007; basement membrane and forms a bridge linking Bru¨ckner 2010). Collagen XXVII forms thin large, banded fibrils, likely fibrils containing nonstriated fibrils (10 nm in diameter) that are collagens I and III (Amenta et al. 2005). distinct from the classical collagen fibrils (Plumb et al. 2007). The microfibrillar structure Network-Forming Collagens of collagen I fibrils has been investigated in situ by X-ray diffraction of rat tail tendons (Orgel Collagen IV forms a network in which four mo- et al. 2006). Collagen I forms supertwisted lecules assemble via their amino-terminal 7S microfibrils of five molecules that interdigitate domain to form tetramers, and two molecules with neighboring microfibrils, leading to the assemble via their carboxy-terminal NC1 do- quasi-hexagonal packing of collagen molecules main to form NC1 dimers. Because the NC1

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domains are trimeric, the NC1 dimer is a hex- of an amino-terminal propeptide followed by amer. The three-dimensional structure of the a short, nonhelical, N-telopeptide, a central tri- hexameric form of the NC1 domain that plays ple helix, a C-telopeptide and a carboxy-ter- a major role in collagen IV assembly and in the minal propeptide. Individual proa chains are stabilization of the collagen [a1(IV)]2a(IV) submitted to numerous posttranslational mod- network has been determined (Sundaramoor- ifications (hydroxylation of proline and lysine thy et al. [2002], PDB ID: 1M3D, Than et al. residues, glycosylation of lysine and hy- [2002], PDB ID: 1LI1). It was hypothesized droxylysine residues, sulfation of tyrosine resi- that collagen IV was stabilized via a covalent dues, Myllyharju and Kivirikko 2004) that are Met-Lys cross-link (Than et al. 2002), but stud- stopped by the formation of the triple helix. ies of a crystal structure of the NC1 domain The heat shock protein 47 (HSP47) binds to (PDB ID: 1T60, 1T61) at a higher resolution procollagen in the endoplasmic reticulum and failed to confirm its existence (Vanacore et al. is a specific molecular chaperone of procollagen 2004). A combination of trypsin digestion and (Sauk et al. 2005). The stabilization of procolla- mass spectrometry analysis has led to the iden- gen triple helix at body temperature requires tification of a S-hydroxylysyl-methionine con- the binding of more than 20 HSP47 molecules necting Met93 and Hyl211 as the covalent per triple helix (Makareeva and Leikin 2007). cross-link that stabilizes the NC1 hexamer of It has been recently suggested that intracellular the [a1(IV)]2a2(IV) network (Vanacore et al. Secreted Protein Acidic and Rich in Cysteine 2005). Other collagen IV networks result from (SPARC) might be a collagen chaperone be- the assembly of the two molecular isoforms cause it binds to the triple-helical domain of [a1(IV)]2a2(IV) and [a5(IV)]2a6(IV), and procollagens and its absence leads to defects in from the assembly of a3(IV)a4(IV)a5(IV) collagen deposition in tissues (Martinek et al. with itself (Borza et al. 2001). Collagens VIII 2007). and X form hexagonal networks in Descemet’s Both propeptides of procollagens are membrane and in hypertrophic cartilage, re- cleaved during the maturation process (Green- spectively. Collagen VI forms beaded filaments span 2005). The N-propeptide is cleaved by and collagen VII assembles into anchoring fibrils procollagen N-proteinases belonging to the connecting the epidermis to the dermis (Ricard- A Disintegrin And Metalloproteinase with Blumetal.2000;GordonandHahn2010;Fig.2). Thrombospondin motifs (ADAMTS) family, Some collagens participate in distinct mo- except the N-propeptide of the proa1(V) chain lecular assemblies. Collagen XVI is a compo- that is cleaved by the procollagen C-proteinase nent of microfibrils containing fibrillin-1 in also termed Bone Morphogenetic Protein-1 skin, whereas it is incorporated into thin, (BMP-1) (Hopkins et al. 2007). BMP-1 cleaves weakly banded fibrils containing collagens II the carboxy-terminal propeptide of procollagens, and XI in cartilage (Kassner et al. 2003). Colla- except the carboxy-terminal propeptide of the gen XII, a fibril-associated collagen, has been proa1(V) chain, that is processed by furin. The reported to be associated with basement mem- telopeptides contain the sites where cross-linking branes in zebra fish (Bader et al. 2009). Supra- occurs. This process is initiated by the oxidative molecular assemblies of several collagens are deamination of lysyl and hydroxylsyl residues able to interact as shown for the anchoring catalyzed by the enzymes of the lysyl oxidase fam- fibrils that are tightly attached to striated colla- ily (Ma¨ki 2009). gen fibrils (Villone et al. 2008). COVALENT CROSS-LINKING COLLAGEN BIOSYNTHESIS OF COLLAGENS Collagen biosynthesis has been extensively stu- Collagen is considered as an elastic protein with died for fibril-forming collagens that are syn- a resilience of 90%. Collagen fibrils are thus thesized as procollagen molecules comprised able to deform reversibly and their mechanical

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properties can be investigated by force spec- types (I/II, I/III, I/V, I I /III, II/IX, II/XI, and troscopy (Gutsmann et al. 2004). The mecha- V/XI) (Eyre et al. 2005; Wu et al. 2009, 2010). nical properties of fibril-forming collagens I, Cross-linking is tissue-specific rather than col- II, III, V, and XI are dependent on covalent lagen-specific. Reducible, bifunctional, cross- cross-links including (1) Disulfide bonds (in links (aldimines and keto-imines) are formed collagens III, IV, VI, VII, and XVI); (2) the in newly synthesized collagens, and they sponta- N1(g-glutamyl)lysine isopeptide, the forma- neously mature into nonreducible trifunctional tion of which is catalyzed by transglutaminase-2 cross-links, pyridinoline and deoxypyridino- in collagens I, III, V/XI, and VII (Esposito and line in bone and cartilage, pyrrole cross-links Caputo 2005); (3) reducible and mature cross- in bone, and histidinohydroxylysinonorleu- links produced via the lysyl oxidase pathway; cine in skin (Eyre and Wu 2005; Robins 2007) and (4) advanced glycation end products (Avery (Fig. 3). Another mature cross-link, an arginyl and Bailey 2006). Furthermore, a hydroxyly- ketoimine adduct called arginoline because of sine-methionine cross-link involving a sulfi- the contribution of one arginine residue, has limine (-S¼N-) bond has been identified in been identified in cartilage (Eyre et al. 2010) collagen IV (Vanacore et al. 2009). (Fig. 3). Cross-link maturation provides added Lysyl-mediated cross-linking involves ly- resistance to shear stress. Pyridinoline and de- sine, hydroxylysine, and histidine residues, oxypyridinoline are used as urinary markers and occurs at the intramolecular and intermo- of bone resorption in patients with bone dis- lecular levels between collagen molecules be- eases such as osteoporosis (Saito and Marumo longing either to the same type or to different 2010).

H HO CH N HC C CH CH2 N HO CNH Arg HC CH HC C NH Arg CH C N N CH 2 N N Lys Lys Pentosidine Glucosepane

HN Arg CHCH2 CH NHCH2 CH CH2 HC 3 2 C C HN N HN N HO CH CH CCNHCH CH CH CH CCH 2 2 2 2 2 HO OH HO CH2 CH Arginoline Histidino-hydroxylysinonorleucine

CH CH

CH2 CH 2 2 2 C CH C CH HO CH CH C N+ 2 CH2 CH2 CH2 HC CH CH C N+ CH CHCH HC 2 2 2 2 CCH 2 HO C CH HO Lysyl-Pyridinoline Hydroxylysyl-Pyridinoline

Figure 3. Collagen cross-links. Lysyl-mediated mature cross-links: argoline, deoxypyridinoline, pyridinoline, and histidinohydroxylysinonorleucine. Advanced glycation endproducts: glucosepane and pentosidine.

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Collagens

Collagens are long-lived proteins that are ectodomain of membrane collagens as soluble modified by glycation (Avery and Bailey 2006). forms. Glycation increases with age and several ad- vanced glycation endproducts act as cross-links COLLAGEN RECEPTORS that contribute to the progressive insolubiliza- tion and to the increased stiffness of collagens Collagens are deposited in the extracellular in aged tissues. Two lysine-arginine cross-links, matrix, but they participate in cell-matrix inter- pentosidine (a fluorescent product formed actions via several receptor families (Heino et al. from ribose), and glucosepane (a nonfluores- 2007, 2009; Humphries et al. 2006; Leitin- cent product formed from glucose) have been ger and Hohenester 2007). They are ligands of identified in collagens. Glucosepane, the most integrins, cell-adhesion receptors that lack in- abundant cross-link in senescent skin collagen, trinsic kinase activities. Collagens bind to integ- is able to cross-link one in five collagen mole- rins containing a b1 subunit combined with cules in the skin of the elderly (Sjo¨berg and one of the four subunits containing an aA Bulterijs 2009). domain (a1, a2, a10, and a11) via GFOGER- like sequences, O being hydroxyproline (Hum- phries et al. 2006; Heino et al. 2007). There are COLLAGEN DEGRADATION other recognition sequences in collagens such Matrix metalloproteinases (MMPs) are zinc- as KGD in the ectodomain of collagen XVII, dependent endopeptidases belonging to the which is recognized by a5b1 and avb1 integrins metzincin superfamily. They participate in but not by the “classical” collagen receptors physiological (development and tissue repair) (Heino et al. 2007). Several bioactive fragments and pathological (tumorigenesis and metasta- resulting from the proteolytic cleavage of sis) processes. Fibril-forming collagens I, II, collagens are ligands of avb3, avb5, a3b1, and III are cleaved by MMP-1 (interstitial colla- and a5b1 integrins (Ricard-Blum and Ballut genase), MMP-8 (neutrophil collagenase), 2011). MMP-13 (collagenase 3) that generate three- Collagens I–III are also ligands of the quarter and one-quarter sized fragments, and dimeric discoidin receptors DDR1 and DDR2 by membrane-anchored MMP-14. MMP-2 is that possess tyrosine kinase activities (Leitinger also able to cleave collagen I (Klein and Bischoff and Hohenester 2007). The major DDR2-bind- 2010). Collagen II is a preferential substrate of ing site in collagens I–III is a GVMGFO motif MMP-13, whereas collagens I and III are pre- (Heino et al. 2009). The crystal structure of a ferentially cleaved by MMP-1 and MMP-8 triple-helical collagen peptide bound to the dis- (Klein and Bischoff 2010). Denatured collagens coidin domain (DS) of DDR2 has provided and collagen IV are degraded by MMP-2 and insight into the mechanism of DDR activation MMP-9 (also known as 72-kDa and 92-kDa that may involve structural changes of DDR2 gelatinases respectively). In contrast to the surface loops induced by collagen binding (Car- [a1 (I)]2a2(I) heterotrimer of collagen I, the afoli et al. 2009) (PDB ID: 2WUH). The activa- [a2(I)]3 homotrimer is not degraded by mam- tion may result from the simultaneous binding malian collagenases. This is because of resis- of both DS domains in the dimer to a single tance of the homotrimer to local triple helix collagen triple helix, or DS domains may bind unwinding by MMP-1 because it has higher tri- collagen independently (Carafoli et al. 2009). ple helix stability near the MMP cleavage site The soluble extracellular domains of DDR1 (Han et al. 2010). MMPs also contribute to and DDR2 regulate collagen deposition in the the release of bioactive fragments or matricryp- extracellular matrix by inhibiting fibrillogenesis tins such as endostatin and tumstatin from (Flynn et al. 2010). DDR2 affects mechanical full-length collagens (Ricard-Blum and Ballut properties of collagen I fibers by reducing their 2011). Another group of enzymes, collectively persistence length and their Young’s modulus called sheddases (Murphy 2009) releases the (Sivakumar and Agarwal 2010).

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Collagens bind to glycoprotein VI (GPVI), a during fibrosis and fibrillogenesis is a new tar- member of the paired immunoglobulin-like re- get to limit fibrosis by blocking telopeptide- ceptor family, on platelets (Heino et al. 2007), mediated interactions of collagen molecules and to the inhibitory leukocyte-associated im- (Chung et al. 2008). Collagens are no longer munoglobulin-like receptor-1 (LAIR-1, Leb- restricted to a triple helix, banded fibrils or to bink et al. 2006). Both receptors recognize the a structural and scaffold role. As stated by Hynes GPO motif in collagens. Ligands of LAIR-1 are (2009) for the extracellular matrix, collagens are fibrillar collagens I, II, and III, and membrane not “just pretty fibrils.” Collagens interact with collagens XIII, XVII, and XXIII. Collagens I cells through several receptors, and their roles and III are functional ligands of LAIR-1 and in- in the regulation of cell growth, differentiation, hibit immune cell activation in vitro. LAIR-1 and migration through the binding of their binds multiple sites on collagens II and III (Leb- receptors is well documented. bink et al. 2009). LAIR-1 and LAIR-2 are high Some collagen types with a restricted tissue affinity receptors for collagens I and III. They distribution exert specific biological functions. bind to them with higher affinity than GPVI Collagen VII is a component of anchoring (Lebbink et al. 2006, Lebbink et al. 2008), but fibrils, and participates in dermal-epidermal three LAIR-1 amino acids central to collagen adhesion. Collagen X, expressed in hypertro- binding are conserved in GPVI (Brondijk et al. phic cartilage, plays a role in endochondral ossi- 2010). Fibril-forming collagens and collagen fication and contributes to the establishment of IV are also ligands of Endo180 (urokinase-type a hematopoietic niche at the chondro-osseous plasminogen activator associated protein), a junction (Sweeney et al. 2010). Collagen XXII member of the macrophage mannose-receptor is present only at tissue junctions such as the family that mediates collagen internalization myotendinous junction in skeletal and heart (Leitinger and Hohenester 2007; Heino et al. muscle (Koch et al. 2004). An association be- 2009). The identification of collagen sequences tween COL22A1 and the level of serum cre- that bind to receptors has benefited from the atinine, the most important biomarker for a Toolkits (overlapping synthetic trimeric pep- quick assessment of kidney function, has been tides encompassing the entire triple-helical detected in a meta-analysis of genome-wide domain of human collagens II and III) devel- data. This association may reflect the biological oped by Farndale et al. (2008). relationship between muscle mass formation and creatinine levels (Pattaro et al. 2010). Colla- gen XXIV is a marker of osteoblast differentia- FUNCTIONS OF COLLAGENS tion and bone formation (Matsuo et al. 2008), Fibrillar collagens are the most abundant colla- and collagen XXVII appears to be restricted gens in vertebrates where they play a structural mainly to cartilage into adulthood. It is associ- role by contributing to the molecular archi- ated with cartilage calcification and could play a tecture, shape, and mechanical properties of role in the transition of cartilage to bone during tissues such as the tensile strength in skin and skeletogenesis (Hjorten et al. 2007). Its involve- the resistance to traction in ligaments (Kadler ment in skeletogenesis has been confirmed in 1995, Ricard-Blum et al. 2000). Several colla- zebra fish where it plays a role in vertebral min- gens, once referred to as “minor” collagens, eralization and postembryonic axial growth are crucial for tissue integrity despite the fact (Christiansen et al. 2009). The a5(VI) chain is that they are present in very small amounts. not expressed in the outer epidermis of patients Collagen IX comprises 1% of collagen in adult with atopic dermatitis, a chronic inflammatory articular cartilage (Martel-Pelletier et al. 2008) skin disorder and a manifestation of allergic and collagen VII, crucial for skin integrity, con- disease, suggesting that it contributes to the stitutes only about 0.001% of total collagens in integrity and function of the epidermis (So¨der- skin (Bruckner-Tuderman et al. 1987). Excess ha¨ll et al. 2007). The association of COL6A5/ collagen is deposited in the extracellular matrix COL29A1 with atopy has been confirmed at

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the genetic level (Castro-Giner et al. 2009). The MATRICRYPTINS OF COLLAGENS gene coding for the a1 chain of collagen XVIII has also been identified as a new potential Bioactive fragments released by proteolytic candidate gene for atopy (Castro-Giner et al. cleavage of collagens regulate a number of phys- 2009). iological and pathological processes such as The four membrane collagens seem to fulfill development, angiogenesis, tumor growth and different functions. Collagen XIII affects bone metastasis, and tissue repair (Nyberg et al. formation and may have a function in coupling 2005; Ricard-Blum and Ballut 2011). These the regulation of bone mass to mechanical use fragments, called matricryptins, increase the (Ylo¨nen et al. 2005). Collagen XVII is a major functional diversity of collagens because most structural component of the hemidesmosome of them possess biological activities that are (Has and Kern 2010), whereas collagen XXIII different from their parent molecule. A single is associated with prostate cancer recurrence collagen type can give rise to several matri- and distant metastases (Banyard et al. 2007). cryptins (collagen IV) (Table 3). Most collagen However, membrane collagens XIII, XVII (Sep- matricryptins are derived from basement mem- pa¨nen et al. 2006), and XXV (Hashimoto et al. brane collagens (collagens IV, VIII, and XVIII) 2002) are expressed in neurons, or neuronal (Table 3) or located in the basement membrane structures, and collagen XXVIII is predomi- zone (collagens XVand XIX) and show antian- nantly expressed in neuronal tissue (Veit et al. giogenic and antitumoral properties (Nyberg 2006). New roles of collagens have been found et al. 2005, Ricard-Blum and Ballut 2011). in the development of the vertebrate nervous Endostatin, the carboxy-terminal fragment of system, when collagen IV plays a role at the neu- collagen XVIII, and tumstatin, the carboxy-ter- romuscular junction as a presynaptic organizer minal domain of the a3(IV) chain, have been (Fox et al. 2007, 2008). Collagen XIX is ex- extensively studied. The extracellular domains pressed by central neurons, and is necessary of membrane collagens released by shedding for the formation of hippocampal synapses because of furin-like proprotein convertases (Su et al. 2010). Several collagens (IV,VI, XVIII, (collagens XIII, XXIII, XXV), or ADAM-9 and XXV) are deposited in the brains of patients and ADAM-10 (collagen XVII) (Franzke et al. with Alzheimer’s disease where they bind to 2009) show paracrine activities and might be the amyloid b peptide. Furthermore, there is considered as matricryptins (Table 3). Matri- genetic evidence of association between the cryptins are potential drugs and Endostar, a COL25A1 gene and risk for Alzheimer’s disease derivative of endostatin, has been approved in (Forsell et al. 2010). Collagen VI seems to pro- 2005 in China for the treatment of nonsmall tect neurons against Ab toxicity (Cheng et al. cell lung cancer in conjunction with chemo- 2009). therapy (Ling et al. 2007).

Table 3. Major matricryptins of collagens. Collagens Collagen a chain Matricryptins Domain Collagen IV a1(IV) chain Arresten NC1 a2(IV) chain Canstatin NC1 a3(IV) chain Tumstatin NC1 a4(IV) chain Tetrastatins 1-3 a5(IV) chain Pentastatins 1-3 a6(IV) chain NC1 a6(IV) NC1 Hexastatins 1-2 Collagen VIII a1(VIII) chain Vastatin NC1 Collagen XV a1(XV) chain Restin NC1 Collagen XVIII a1(XVIII) chain Endostatin NC1 Collagen XIX a1(XIX) chain NC1

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GENETIC AND ACQUIRED DISEASES is the major autoantigen of the skin blister- OF COLLAGENS ing disease bullous pemphigoid (Franzke et al. 2005). The NC1 domain of the a3(IV) chain Several autoimmune disorders involve auto- contains the epitopes recognized by the anti- antibodies directed against collagens. Collagen glomerular basement membrane antibodies VII is the autoantigen of epidermolysis bullosa found in patients with Goodpasture syndrome acquisita (Ishii et al. 2010), and collagen XVII characterized by glomerulonephritis and lung

Table 4. Genetic diseases because of mutations in collagen genes. Gene Disease References, databases COL1A1 Osteogenesis imperfecta Marini et al. (2007) COL1A2 Ehlers–Danlos syndrome Dalgleish (1997, 1998) www.le.ac.uk/genetics/collagen Bodian and Klein (2009) http://collagen.stanford.edu/ COL2A1 Spondyloepiphyseal dysplasia Bodian and Klein (2009) Spondyloepimetaphyseal dysplasia, http://collagen.stanford.edu/ Achondrogenesis, hypochondrogenesis Kniest dysplasia, Stickler syndrome COL3A1 Ehlers–Danlos syndrome Dalgleish (1997, 1998) www.le.ac.uk/genetics/collagen Bodian and Klein (2009) http://collagen.stanford.edu/ COL4A1 Familial porencephaly Van Agtmael and Bruckner-Tuderman (2010) Hereditary angiopathy with nephropathy, aneurysms and muscle cramps syndrome COL4A3 Alport syndrome Van Agtmael and Bruckner-Tuderman (2010) COL4A4 Benign familial haematuria COL4A5 Alport syndrome Bateman et al. (2009), Van Agtmael and COL4A6 Leiomyomatosis Bruckner-Tuderman (2010) COL5A1 Ehlers–Danlos syndrome Callewaert et al. (2008) COL5A2 COL6A1 Bethlem myopathy Lampe and Bushby (2005) COL6A2 Ullrich congenital muscular COL6A3 dystrophy COL7A1 Dystrophic epidermolysis bullosa Fine (2010) COL8A2 Corneal endothelial dystrophies Bateman et al. (2009) COL9A1 Multiple epiphyseal dysplasia Carter and Raggio (2009) COL9A2 COL9A3 Multiple epiphyseal dysplasia Carter and Raggio (2009) Autosomal recessive Stickler syndrome COL10A1 Schmid metaphyseal chondrodysplasia Grant (2007) COL11A1 Stickler syndrome Carter and Raggio (2009) Marshall syndrome COL11A2 Stickler syndrome Carter and Raggio (2009) Marshall syndrome Otospondylomegaepiphyseal dysplasia Deafness COL17A1 Junctional epidermolysis bullosa-other Has and Kern (2010) COL18A1 Knobloch syndrome Nicolae and Olsen (2010)

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hemorrhage (Khoshnoodi et al. 2008). Bronchio- be composed of cell interaction domains and litis obliterans syndrome, the most common matrix interaction domains (Sweeney et al. cause of lung transplant failure, is associated 2008). Defining the structures and functions with a strong cellular immune response to colla- of collagen domains along the collagen fibril gen V (Burlingham et al. 2007). will provide new insights into collagen fibril Many disorders are caused by mutations in functions, and into their possible modulation, the genes coding for collagen a chains (Table 4) specifically in fibroproliferative diseases where (Lampe and Bushby 2005; Callewaert et al. collagen fibrillogenesis is a new target to limit 2008; Bateman et al. 2009; Carter and Raggio fibrosis (Chung et al. 2008). The binding force 2009; Fine 2010). Mutations of collagen I, II, between collagen and other proteins can be cal- and III genes are catalogued in the human culated by atomic microscopy, and these meas- collagen mutation database (Dalgleish 1997, urements, in addition to kinetics, affinity and 1998) and in the COLdb database that links thermodynamics data, could be used to hier- genetic data to molecular function in fibrillar archize interactions participating in biological collagens (Bodian and Klein 2009). Regions processes. Interaction data on collagens and rich in osteogenesis imperfecta lethal mutations other extracellular biomolecules are stored in a align with collagen binding sites for integrins database called MatrixDB (http://matrixdb. and proteoglycans in the helical domain of ibcp.fr) (Chautard et al. 2009). These data can type I collagen (Marini et al. 2007). The mu- be used to build extracellular interaction net- tations affect the extracellular matrix by de- works of a molecule, a tissue or a disease and creasing the amount of secreted collagen(s), to make functional hypothesis. New tools to impairing molecular and supramolecular as- identify binding partners of a protein (protein sembly through the secretion of a mutant colla- and glycosaminoglycan arrays probed by sur- gen, or by inducing endoplasmic reticulum face plasmon resonance imaging (Faye et al. stress and the unfolded protein response (Bate- 2009, 2010), and a proteomics workflow to man et al. 2009). isolate complexes associated with integrin adhe- sion receptors (Humphries et al. 2009), will be helpful in deciphering the functions of colla- CONCLUDING REMARKS gens at the systems biology level. During the last 40 years, the collagen field has evolved from collagen chemistry to cell ACKNOWLEDGMENTS therapy as recounted by Michael Grant (2007). Twenty-eight collagen types have been identi- Romain Salza (UMR 5086 CNRS-University fied and characterized at the molecular level. Lyon 1, France) is gratefully acknowledged for Their functions have been determined either drawing the figures of the manuscript, and through direct assays or from the generation David J. Hulmes (UMR 5086 CNRS - University of knockout mice and the knowledge of defects Lyon 1, France) for his critical reading of the occurring in tissues of patients with genetic manuscript and his suggestions. diseases because of mutation(s) in genes cod- ing for collagens. Cell therapy gives promising results for recessive dystrophic epidermolysis REFERENCES bullosa (Kern et al. 2009; Conget et al. 2010), Amenta PS, Scivoletti NA, Newman MD, Sciancalepore JP, and osteogenesis imperfecta (Niyibizi and Li Li D, Myers JC. 2005. Proteoglycan-collagen XV in human tissues is seen linking banded collagen fibers sub- 2009). To understand how collagens work in jacent to the basement membrane. J Histochem Cytochem a concerted fashion with their extracellular 53: 165–176. and cell-surface partners, a global, integrative Ansorge HL, Meng X, Zhang G, Veit G, Sun M, Klement JF, approach is needed. Ligand-binding sites, func- Beason DP, Soslowsky LJ, Koch M, Birk DE. 2009. Type XIV collagen regulates fibrillogenesis: premature collagen tional domains and mutations have been fibril growth and tissue dysfunction in null mice. J Biol mapped on the collagen I fibril that appears to Chem 284: 8427–8438.

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The Collagen Family

Sylvie Ricard-Blum

Cold Spring Harb Perspect Biol 2011; doi: 10.1101/cshperspect.a004978 originally published online December 15, 2010

Subject Collection Extracellular Matrix Biology

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