Collagen trimers in triple-helical form, referred to as procollagen or collagen molecules, are exported from the ER and trafficked through the Golgi network before secretion into the extracellular space. For fibrillar collagens namely types I, II, III, V, XI, XXIV and XXVII (Gordon & Hahn 2010, Ricard-Blum 2011) secretion is concomitant with processing of the N and C terminal collagen propeptides. These processed molecules are known as tropocollagens, considered to be the units of higher order collagen structures. They form within the extracellular space via a process that can proceed spontaneously, but in the cellular environment is regulated by many collagen binding proteins such as the FACIT (Fibril Associated Collagens with Interrupted Triple helices) family collagens and Small Leucine-Rich Proteoglycans (SLRPs). The architecture formed ultimately depends on the collagen subtype and the cellular conditions. Structures include the well-known fibrils and fibres formed by the major structural collagens type I and II plus several different types of supramolecular assembly (Bruckner 2010). The mechanical and physical properties of tissues depend on the spatial arrangement and composition of these collagen-containing structures (Kadler et al. 1996, Shoulders & Raines 2009, Birk & Bruckner 2011).
Fibrillar collagen structures are frequently heterotypic, composed of a major collagen type in association with smaller amounts of other types, e.g. type I collagen fibrils are associated with types III and V, while type II fibrils frequently contain types IX and XI (Wess 2005). Fibres composed exclusively of a single collagen type probably do not exist, as type I and II fibrils require collagens V and XI respectively as nucleators (Kadler et al. 2008, Wenstrup et al. 2011). Much of the structural understanding of collagen fibrils has been obtained with fibril-forming collagens, particularly type I, but some central features are believed to apply to at least the other fibrillar collagen subtypes (Wess 2005). Fibril diameter and length varies considerably, depending on the tissue and collagen types (Fang et al. 2012). The reasons for this are poorly understood (Wess 2005).
Some tissues such as skin have fibres that are approximately the same diameter while others such as tendon or cartilage have a bimodal distribution of thick and thin fibrils. Mature type I collagen fibrils in tendon are up to 1 cm in length, with a diameter of approx. 500 nm. An individual fibrillar collagen triple helix is less than 1.5 nm in diameter and around 300 nm long; collagen molecules must assemble to give rise to the higher-order fibril structure, a process known as fibrillogenesis, prevented by the presence of C-terminal propeptides (Kadler et al. 1987). In electron micrographs, fibrils have a banded appearance, due to regular gaps where fewer collagen molecules overlap, which occur because the fibrils are aligned in a quarter-stagger arrangement (Hodge & Petruska 1963). Collagen microfibrils are believed to have a quasi-hexagonal unit cell, with tropocollagen arranged to form supertwisted, right-handed microfibrils that interdigitate with neighbouring microfibrils, leading to a spiral-like structure for the mature collagen fibril (Orgel et al. 2006, Holmes & Kadler 2006).
Neighbouring tropocollagen monomers interact with each other and are cross-linked covalently by lysyl oxidase (Orgel et al. 2000, Mäki 2006). Mature collagen fibrils are stabilized by lysyl oxidase-mediated cross-links. Hydroxylysyl pyridinoline and lysyl pyridinoline cross-links form between (hydroxy) lysine and hydroxylysine residues in bone and cartilage (Eyre et al. 1984). Arginoline cross-links can form in cartilage (Eyre et al. 2010); mature bovine articular cartilage contains roughly equimolar amounts of arginoline and hydroxylysyl pyridinoline based on peptide yields. Mature collagen fibrils in skin are stabilized by the lysyl oxidase-mediated cross-link histidinohydroxylysinonorleucine (Yamauch et al. 1987). Due to the quarter-staggered arrangement of collagen molecules in a fibril, telopeptides most often interact with the triple helix of a neighbouring collagen molecule in the fibril, except for collagen molecules in register staggered by 4D from another collagen molecule. Fibril aggregation in vitro can be unipolar or bipolar, influenced by temperature and levels of C-proteinase, suggesting a role for the N- and C- propeptides in regulation of the aggregation process (Kadler et al. 1996). In vivo, collagen molecules at the fibril surface may retain their N-propeptides, suggesting that this may limit further accretion, or alternatively represents a transient stage in a model whereby fibrils grow in diameter through a cycle of deposition, cleavage and further deposition (Chapman 1989).
In vivo, fibrils are often composed from more than one type of collagen. Type III collagen is found associated with type I collagen in dermal fibrils, with the collagen III on the periphery, suggesting a regulatory role (Fleischmajer et al. 1990). Type V collagen associates with type I collagen fibrils, where it may limit fibril diameter (Birk et al. 1990, White et al. 1997). Type IX associates with the surface of narrow diameter collagen II fibrils in cartilage and the cornea (Wu et al. 1992, Eyre et al. 2004). Highly specific patterns of crosslinking sites suggest that collagen IX functions in interfibrillar networking (Wess 2005). Type XII and XIV collagens are localized near the surface of banded collagen I fibrils (Nishiyama et al. 1994). Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Gordon & Hahn 2010). Collagen XV, a member of the multiplexin family, is almost exclusively associated with the fibrillar collagen network, in very close proximity to the basement membrane. In human tissues collagen XV is seen linking banded collagen fibers subjacent to the basement membrane (Amenta et al. 2005). Type XIV collagen, SLRPs and discoidin domain receptors also regulate fibrillogenesis (Ansorge et al. 2009, Kalamajski et al. 2010, Flynn et al. 2010).
Collagen IX is cross-linked to the surface of collagen type II fibrils (Eyre et al. 1987). Type XII and XIV collagens are found in association with type I (Walchli et al. 1994) and type II (Watt et al. 1992, Eyre 2002) fibrils in cartilage. They are thought to associate non-covalently via their COL1/NC1 domains (Watt et al. 1992, Eyre 2002).
Some non-fibrillar collagens form supramolecular assemblies that are distinct from typical fibrils. Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptides are then removed by Bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers aggregate laterally. Collagens VIII and X form hexagonal networks and collagen VI forms beaded filament (Gordon & Hahn 2010, Ricard-Blum et al. 2011).
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Hashizume H, Hitomi J, Ushiki T.; ''Growth of collagen fibrils produced by human osteosarcoma cells: high-resolution scanning electron microscopy.''; PubMedEurope PMCScholia
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Schmid TM, Linsenmayer TF.; ''Immunoelectron microscopy of type X collagen: supramolecular forms within embryonic chick cartilage.''; PubMedEurope PMCScholia
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Lysine residues can be converted to allysine by lysyl oxidase. In this representative reaction a single lysine residue in each collagen chain is shown as converted to allysine (Pinnell et al. 1968).
Hydroxylysines residues can be converted to hydroxyallysines by lysyl oxidase. In this representative reaction a single hydroxylysine residue in each collagen chain is shown as converted to hydroxyallysine (Pinnell et al. 1968, Siegel 1979).
Type XVII collagen is a component of hemidesmosomes (HDs) (Has & Kern 2010). It associates with integrin alpha6beta4 (a6b4) (Hopkinson et al. 1999). The extracellular region of a6b4 extends from the cell membrane into the basement membrane to bind laminins, with a preference for laminin-332 (Hopkinson & Jones 2000, Sugawara et al. 2008), which is a component of anchoring fibrils. Laminins are complex glycoproteins, consisting of alpha, beta and gamma chains bound into a cross-shaped molecule. Laminin-332 is a complex of alpha-3, beta-2 and gamma-2 subunits. The cytoplasmic domain of integrin beta-4 interacts with other hemidesmosomal components, plectrin and BPAG1. The interaction of a6b4 and plectrin is likely to be the initial step in HD formation (de Pereda et al. 2009). The cytoplasmic domain of collagen type XVII (BP180) binds to integrin beta-4, plectin and BPAG1 (Hopkinson & Jones 2000, Koster et al. 2003). The transmembrane protein CD151 (tetraspanin-24) associates with a6b4 (Sterk et al. 2002) and is essential for the correct assembly of basement membranes in human kidney and skin, possibly having a role in integrin alpha-3 maturation and cell surface expression (Karamatic Crew et al. 2003).
Collagens XV and XVIII are basement membrane associated collagens that can be cleaved to generate the antiangiogenic peptides restin (endostatin-XV) and endostatin (endostatin-XVIII), respectively (O'Reilly et al. 1997, Ramachandran et al. 1997, Sasaki et al. 2000). Endostatin fragments of differing molecular size (14-30 kDa) have been identified in vivo. Furthermore the C-terminal domains of several other collagens (IV, VIII, XIX) have anti-angiogenic and anti-tumoral activities (Ricard-Blum & Ballut 2011). Several proteases are able to generate endostatin from collagen XVIII including MMP-3, -7, -9, -13 and -20 and cathepsins B, V, S and L (Heljasvaara et al. 2005, Ma et al. 2007, Veillard et al. 2011). Endostatin inhibits proliferation of endothelial cells, angiogenesis and tumor growth in vivo (O'Reilly et al. 1997).
Lysyl-pyridinoline (L-Pyr) cross-links are formed from two hydroxylysine residues and a lysine residue (LKNL plus a further hydroxyallysine contributed by HLKNL), found mostly in calcified tissues (Bailey et al. 1998).
Hydroxylysyl-pyridinoline (HL-Pyr) is formed from three hydroxylysine residues, (HLKNL plus a further hydroxyallysine donated by a second HLKNL). It predominates in highly hydroxylated collagens such as type II collagen in cartilage.
Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Ansorge et al. 2009, Gordon & Hahn 2010). Type XII and XIV colalgens are found in association with type I (Walchli et al. 1994) and type II (Watt et al. 1992, Eyre 2002).
Collagen fibrils are the principal tensile element of the extracellular matrix in a wide range of animal connective tissues. They have a 67 nm axial periodicity in most tissues, 65 nm in vertebrate skin, and are near-circular in transverse section. Fibril diameter depends both on tissue type and stage of development, covering a range of 20-500 nm in vertebrates. Fibril length is less well characterised but fibrils with lengths in the range 1-100 micrometres have been isolated.
Fibril formation is spontaneous (Fallas et al. 2010, Birk & Brückner 2011), but influenced by developmental state and the cellular environment. Several models have been proposed including the simple surface nucleation and propagation (SNAP) model (Trotter et al. 2000) but the mechanism of fibril assembly and regulation of fibril diameter and length are not completely understood (Holmes et al. 2001, Banos et al. 2008). Fibrils frequently contain more than one type of collagen, and the outer surface of fibrils frequently interacts with proteoglycans, fine-tuning its structural and signaling properties (Wess 2005, Kalamajski & Oldberg 2010, Ricard-Blum et al. 2011).
Individual fibril-forming collagen molecules are around 300nm in length. Complete fibrils exhibit a 67 nm periodicity, seen with many different imaging methods. This is due to a staggered overlap of molecules which leads to regions where fewer molecules overlap with a periodicity of 67 nm (Hodge & Petruska 1963, Wess 2005). Laterally, molecules are believed to be packed into a quasi-hexagonal structure (Trus & Piez 1980) resulting in locally ordered crystalline regions interspersed with disordered regions across the lateral plane of the fibril (Hulmes 2002). Interactions between molecules stabilize the fibril, including the formation of divalent and subsequently trivalent crosslinks, unique to collagen, that involve lysine or hydroxylysine residues.
Collagen VII triple-helices form an anti-parallel dimer, associating through disulfide bonds formed in a 60-nm overlap (NC2 domain) of the amino terminal triple helical ends. A portion of this region is proteolytically removed (Morris et al. 1986, Chen et al. 2001) prior to aggregation of dimers into anchoring fibrils (Lundstrum et al. 1986).
Collagens IV, VI, VIII and X form open networks. Type IV networks are irregular. Type VIII and X form hexagonal networks. Type VI collagen forms tetramers which aggregate linearly to form beaded filaments, but also associates laterally through the globular domains so forming a network (Baldock et al. 2003, Knupp et al. 2006, ). Type IV collagen is the predominant collagen type in basement membranes (Parkin et al. 2011). It assembles into three distinct networks with differing combinations of alpha chains, namely alpha1.alpha1.alpha2, alpha3.alpha4.alpha5 and alpha1.alpha2.alpha5.alpha6, (Siebold et al. 1988, Gunwar et al. 1998, Borza et al. 2001), the last of these forms through the association of alpha5.alpha5.alpha6 triple-helical protomers and alpha1.alpha1.alpha2 protomers, interacting tail-to-tail at the retained NC1 domains. Further associations are formed by tetramerization of the 7S domain at the N terminus (Timpl et al. 1981, Siebold et al. 1987). These interactions are the most significant for network formation, but a third interaction occurs whereby type IV collagen dimers interact through lateral association (Yurchenco & Furthmayr 1984, Yurchenco & Ruben 1987, Yurchenko & Patton 2009). Collagen type VI forms tetramers and subsequently several types of higher-order structure (Ball et al. 2001, Beecher et al. 2011) that are probably influenced by the association of other matrix constituents such as hyaluronan (Kielty et al. 1992), fibrillin (Ueda & Yue 2003), biglycan and decorin (Wiberg et al. 2001).
Type VIII collagen forms a hexagonal lattice in Descemet's membrane (Shuttleworth 1997). These are thought to be derived from tetrahedral structures that form when 4 type VIII molecules associate via hydrophobic patches on their C-termini, which then associate via their N-terminals (Stephan et al. 2004). Type X collagen is very similar to type VIII and in vitro forms hexagonal arrays, believed to arise from interactions of the globular domains (Kwan et al. 1991, Jacenko et al. 2001). In vivo type X collagen is found associated with cartilage fibrils in the form of fine filaments (Schmidt & Linsenmayer 1990), which may represent hexagonal lattices that have collapsed during sample preparation (Gordon & Hahn 2010).
Bone morphogenetic protein-1 (BMP1) cleaves the C-terminal propeptide from human procollagen VII within the NC2 domain at the BMP1 consensus cleavage site SYAA|DTAG. Mammalian tolloid-like (mTLL)-1 and -2 can substitute for BMP1 (Ratttenholl et al. 2002).
Hydroxyallysine and hydroxylysine can react forming the Schiff base, which spontaneously undergoes an Amadori rearrangement resulting in the ketoimine cross-link hydroxylysino-5-ketonorleucine (HLKNL). This is much more stable than the aldimine crosslinks (Bailey et al. 1998).
Allysine residues condense with hydroxylysine residues to form the aldimine dehydro-hydroxylysino-norleucine (deH-HLNL), first identified by Bailey & Peach (1968).
Fibrils are components of larger suprafibrillar structures, fibres. The organisation of fibrils varies between tissues; in the cornea fibrils are arranged in parallel within layers but layers have different orientations. In articular cartilage, fibrils are arranged in mostly parallel layers (Wess 2005). Interactions between fibrils are thought to be largely mediated by surface-associated macromolecules, such as anionic glycosaminoglycans (GAGs) and small leucine-rich proteoglycans such as decorin.
Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptides are then removed by bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers laterally aggregate (Gordon & Hahn 2010).
Histidino-hydroxylysinonorleucine (HHL) cross-links, formed when deH-HLNL reacts with a histidine residue, have been identified in skin and cornea (Yamauchi et al. 1987, 1996, Okada et al. 1997).
In bone, cross-links are formed between telopeptide hydroxallysine residues and helical lysines (Robins & Bailey 1975). The resulting Schiff base undergoes Amadori rearrangement to form lysino-5-ketonorleucine (LKNL).
Trivalent collagen cross-links can form as pyrroles. Hydroxylysyl-Pyrrole (HL-Pyrrole) is formed when Hydroxylysino-ketonorleucine (HLKNL) reacts with hydroxylysino-norleucine (deH-HLNL) (Eyre et al. 2008). The mechanism of pyrrole cross-links has been revised to a structure based on 3-hydroxypyrrole, rather than a pyrrole lacking a hydroxyl on the ring as depicted earlier (Bailey et al. 1998).
In vivo type X collagen is found associated with cartilage fibrils in the form of fine filaments (Schmidt & Linsenmayer 1990), which may represent hexagonal lattices that have collapsed during sample preparation (Gordon & Hahn 2010).
Trivalent collagen cross-links can also form as pyrroles. Lysyl-Pyrrole (L-Pyrrole) is formed when Lysino-ketonorleucine (LKNL) reacts with Hydroxylysino-norleucine (deH-HLNL) (Eyre et al. 2008), with structures based on a 3-hydroxypyrrole, believed to be the core structure of the pyrrole cross-links in bone collagen, rather than a pyrrole lacking a hydroxyl on the ring as depicted earlier.
Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Gordon & Hahn 2010, Ricard-Blum et al. 2011). Collagen IX cross-linked to the surface of collagen type II fibrils is thought to both regulate fibril diameter and stabilize interfibrillar connections (Eyre et al. 2004). An alternative model suggests that collagen II and XI form a biological alloy (Blaschke et al. 2000).
Type XI collagen molecules are cross-linked by lysyl oxidase-mediated bonds (Wu & Eyre 1995) primarily in a head-to-tail manner (Eyre et al. 2006). Homopolymers of type XI collagen can form in vitro (Bruckner & van der Rest 1994, Blaschke et al. 2000). Type XI collagen molecules can cross-link with type II collagen forming heterofibrils (Eyre & Wu 2004, 2005).
Allysine residues can condense with lysine residues forming dehydro-lysinonorleucine (deH-LNL) cross-links. In this representative reaction, all allysine residues are shown as converted to deH-LNL though partial conversion, or conversion to other cross-linked forms is possible (Reiser et al. 1992, Bailey & Peach 1968).
Lysyl oxidase (LOX) is secreted to the extracellular space in an inactive, proenzyme form (proLOX). This is proteolytically cleaved between Gly168 and Asp169 generating the mature 32-kDa enzyme. The activating proteinase is Bone morphogenetic protein 1 (BMP1), also called Procollagen C-proteinase (Cronshaw et al. 1995, Panchenko et al. 1996). Other extracellular proteases, including the BMP1 variant mammalian tolloid, tolloid-like (TLL) 1 and TLL2 proteases cleave proLOX at the correct physiological site but with lower efficiency (Uzel et al. 2001).
Anchoring fibrils are structures in skin that consist largely of collagen VII. They extend from the epidermal basement membrane to the dermal stroma where they connect with reticular fibre bundles, largely composed of collagen III (Fleischmajer et al. 1980). The long loop region of collagen VII entraps fibrillar collagens in the papillary dermis (Burgeson 1993). Type VII collagen binds laminin-332 (laminin-5) through the beta3 short arm, and also binds both type IV collagen and interstitial banded collagen fibrils - represented here by their major constituent, collagen I (Nakishima et al. 2005, Brittingham et al. 2006, Villone et al. 2008). Mutations of collagen VII are a cause of dystrophic epidermolysis bullosa, a blistering skin disease where separation occurs in the dermis at the level of anchoring fibrils (Chung & Uitto 2010, Uitto et al. 2010).
Fibrillar collagen structures are frequently heterotypic, composed of a major collagen type in association with smaller amounts of other types, e.g. type I collagen fibrils are associated with types III and V, while type II fibrils frequently contain types IX and XI (Wess 2005). Fibres composed exclusively of a single collagen type probably do not exist, as type I and II fibrils require collagens V and XI respectively as nucleators (Kadler et al. 2008, Wenstrup et al. 2011). Much of the structural understanding of collagen fibrils has been obtained with fibril-forming collagens, particularly type I, but some central features are believed to apply to at least the other fibrillar collagen subtypes (Wess 2005). Fibril diameter and length varies considerably, depending on the tissue and collagen types (Fang et al. 2012). The reasons for this are poorly understood (Wess 2005).
Some tissues such as skin have fibres that are approximately the same diameter while others such as tendon or cartilage have a bimodal distribution of thick and thin fibrils. Mature type I collagen fibrils in tendon are up to 1 cm in length, with a diameter of approx. 500 nm. An individual fibrillar collagen triple helix is less than 1.5 nm in diameter and around 300 nm long; collagen molecules must assemble to give rise to the higher-order fibril structure, a process known as fibrillogenesis, prevented by the presence of C-terminal propeptides (Kadler et al. 1987). In electron micrographs, fibrils have a banded appearance, due to regular gaps where fewer collagen molecules overlap, which occur because the fibrils are aligned in a quarter-stagger arrangement (Hodge & Petruska 1963). Collagen microfibrils are believed to have a quasi-hexagonal unit cell, with tropocollagen arranged to form supertwisted, right-handed microfibrils that interdigitate with neighbouring microfibrils, leading to a spiral-like structure for the mature collagen fibril (Orgel et al. 2006, Holmes & Kadler 2006).
Neighbouring tropocollagen monomers interact with each other and are cross-linked covalently by lysyl oxidase (Orgel et al. 2000, Mäki 2006). Mature collagen fibrils are stabilized by lysyl oxidase-mediated cross-links. Hydroxylysyl pyridinoline and lysyl pyridinoline cross-links form between (hydroxy) lysine and hydroxylysine residues in bone and cartilage (Eyre et al. 1984). Arginoline cross-links can form in cartilage (Eyre et al. 2010); mature bovine articular cartilage contains roughly equimolar amounts of arginoline and hydroxylysyl pyridinoline based on peptide yields. Mature collagen fibrils in skin are stabilized by the lysyl oxidase-mediated cross-link histidinohydroxylysinonorleucine (Yamauch et al. 1987). Due to the quarter-staggered arrangement of collagen molecules in a fibril, telopeptides most often interact with the triple helix of a neighbouring collagen molecule in the fibril, except for collagen molecules in register staggered by 4D from another collagen molecule. Fibril aggregation in vitro can be unipolar or bipolar, influenced by temperature and levels of C-proteinase, suggesting a role for the N- and C- propeptides in regulation of the aggregation process (Kadler et al. 1996). In vivo, collagen molecules at the fibril surface may retain their N-propeptides, suggesting that this may limit further accretion, or alternatively represents a transient stage in a model whereby fibrils grow in diameter through a cycle of deposition, cleavage and further deposition (Chapman 1989).
In vivo, fibrils are often composed from more than one type of collagen. Type III collagen is found associated with type I collagen in dermal fibrils, with the collagen III on the periphery, suggesting a regulatory role (Fleischmajer et al. 1990). Type V collagen associates with type I collagen fibrils, where it may limit fibril diameter (Birk et al. 1990, White et al. 1997). Type IX associates with the surface of narrow diameter collagen II fibrils in cartilage and the cornea (Wu et al. 1992, Eyre et al. 2004). Highly specific patterns of crosslinking sites suggest that collagen IX functions in interfibrillar networking (Wess 2005). Type XII and XIV collagens are localized near the surface of banded collagen I fibrils (Nishiyama et al. 1994). Certain fibril-associated collagens with interrupted triple helices (FACITs) associate with the surface of collagen fibrils, where they may serve to limit fibril fusion and thereby regulate fibril diameter (Gordon & Hahn 2010). Collagen XV, a member of the multiplexin family, is almost exclusively associated with the fibrillar collagen network, in very close proximity to the basement membrane. In human tissues collagen XV is seen linking banded collagen fibers subjacent to the basement membrane (Amenta et al. 2005). Type XIV collagen, SLRPs and discoidin domain receptors also regulate fibrillogenesis (Ansorge et al. 2009, Kalamajski et al. 2010, Flynn et al. 2010).
Collagen IX is cross-linked to the surface of collagen type II fibrils (Eyre et al. 1987). Type XII and XIV collagens are found in association with type I (Walchli et al. 1994) and type II (Watt et al. 1992, Eyre 2002) fibrils in cartilage. They are thought to associate non-covalently via their COL1/NC1 domains (Watt et al. 1992, Eyre 2002).
Some non-fibrillar collagens form supramolecular assemblies that are distinct from typical fibrils. Collagen VII forms anchoring fibrils, composed of antiparallel dimers that connect the dermis to the epidermis (Bruckner-Tuderman 2009). During fibrillogenesis, the nascent type VII procollagen molecules dimerize in an antiparallel manner. The C-propeptides are then removed by Bone morphogenetic protein 1 (Rattenholl et al. 2002) and the processed antiparallel dimers aggregate laterally. Collagens VIII and X form hexagonal networks and collagen VI forms beaded filament (Gordon & Hahn 2010, Ricard-Blum et al. 2011).
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Fibril formation is spontaneous (Fallas et al. 2010, Birk & Brückner 2011), but influenced by developmental state and the cellular environment. Several models have been proposed including the simple surface nucleation and propagation (SNAP) model (Trotter et al. 2000) but the mechanism of fibril assembly and regulation of fibril diameter and length are not completely understood (Holmes et al. 2001, Banos et al. 2008). Fibrils frequently contain more than one type of collagen, and the outer surface of fibrils frequently interacts with proteoglycans, fine-tuning its structural and signaling properties (Wess 2005, Kalamajski & Oldberg 2010, Ricard-Blum et al. 2011).
Individual fibril-forming collagen molecules are around 300nm in length. Complete fibrils exhibit a 67 nm periodicity, seen with many different imaging methods. This is due to a staggered overlap of molecules which leads to regions where fewer molecules overlap with a periodicity of 67 nm (Hodge & Petruska 1963, Wess 2005). Laterally, molecules are believed to be packed into a quasi-hexagonal structure (Trus & Piez 1980) resulting in locally ordered crystalline regions interspersed with disordered regions across the lateral plane of the fibril (Hulmes 2002). Interactions between molecules stabilize the fibril, including the formation of divalent and subsequently trivalent crosslinks, unique to collagen, that involve lysine or hydroxylysine residues.
Type VIII collagen forms a hexagonal lattice in Descemet's membrane (Shuttleworth 1997). These are thought to be derived from tetrahedral structures that form when 4 type VIII molecules associate via hydrophobic patches on their C-termini, which then associate via their N-terminals (Stephan et al. 2004). Type X collagen is very similar to type VIII and in vitro forms hexagonal arrays, believed to arise from interactions of the globular domains (Kwan et al. 1991, Jacenko et al. 2001). In vivo type X collagen is found associated with cartilage fibrils in the form of fine filaments (Schmidt & Linsenmayer 1990), which may represent hexagonal lattices that have collapsed during sample preparation (Gordon & Hahn 2010).