Elsevier

Micron

Volume 32, Issue 3, April 2001, Pages 223-237
Micron

Review
Type V collagen: heterotypic type I/V collagen interactions in the regulation of fibril assembly

https://doi.org/10.1016/S0968-4328(00)00043-3Get rights and content

Abstract

Type V collagen is a quantitatively minor fibrillar collagen with a broad tissue distribution. The most common type V collagen isoform is α1(V)2 α2(V) found in cornea. However, other isoforms exist, including an [α1(V)α2(V)α3(V)] form, an α1(V)3 homotrimer and hybrid type V/XI forms. The functional role and fibrillar organization of these isoforms is not understood. In the cornea, type V collagen has a key role in the regulation of initial fibril assembly. Type I and type V collagen co-assemble into heterotypic fibrils. The entire triple-helical domain of the type V collagen molecules is buried within the fibril and type I collagen molecules are present along the fibril surface. The retained NH2-terminal domains of the type V collagen are exposed at the surface, extending outward through the gap zones. The molecular model of the NH2-terminal domain indicates that the short α helical region is a flexible hinge-like region allowing the peptide to project away from the major axis of the molecule; the short triple-helical regions serve as an extension through the hole zone, placing the tyrosine-rich domain at the surface. The assembly of early, immature fibril intermediates (segments) is regulated by the NH2-terminal domain of type V collagen. These NH2-terminal domains alter accretion of collagen molecules onto fibrils and therefore lateral growth. A critical density would favor the initiation of new fibrils rather than the continued growth of existing fibrils. Other type V collagen isoforms are likely to have an important role in non-cornea tissues. This role may be mediated by supramolecular aggregates different from those in the corneal stroma or by an alteration of the interactions mediated by tissue-specific type V collagen domains generated by different isoforms or aggregate structures. Presumably, the aggregate structure or specific domains are involved in the regionalization of fibril-associated macromolecules necessary for the tissue-specific regulation of later fibril growth and matrix assembly stages.

Introduction

Vertebrates contain at least 20 different collagen types that comprise a large heterogeneous family (Prockop and Kivirikko, 1995). These are found with unique molecular structures, tissue-specific macromolecular structures, organizations and functions, that arise during development with defined temporal and spatial patterns. In addition to their structural roles, collagens potentially have numerous developmental and physiological functions. The assembly of complex collagenous matrices define tissue structure and function during morphogenesis, growth, repair and in pathobiological processes.

The fibril-forming collagens are the most abundant and are the major components of tissues such as cornea, tendon, dermis, bone, and cartilage. This class includes collagen types I, II, III, V, and XI. These collagen types contain an uninterrupted triple helical region containing the primary sequence repeat, Gly-X-Y and can form striated fibrils with a 67 nm repeat. The individual molecules are staggered about one-quarter their length, and a “gap zone” is present between the amino terminus of one molecule and the carboxy terminus of the next. The “overlap zone” is the region where molecular overlap is complete (Linsenmayer, 1991). The synthesis of collagen molecules and their association to form fibrils requires a number of sequential post-translational events that are common to all fibrillar collagens (Linsenmayer, 1991, Prockop and Kivirikko, 1995). These include intracellular processes such as hydroxylation and glycosylation and extracellular ones such as procollagen processing and cross-linking. The gap zone has been implicated in a variety of molecular interactions. For instance, it may be necessary for the enzymatic formation of aldehyde-derived cross-links. Lysyl oxidase acts to form these cross-links between the amino and carboxyl terminal, non-triple helical extension peptides of molecules after they have aggregated into the native fibrillar form (Siegel, 1974). The hole zone may allow enzyme access and provide a site where the telopeptides have the required alignment. It also may be the site where functional domains of molecules embedded within the fibril present themselves on the fibril surface, such as the amino propeptides.

Fibril assembly is a multistep process and, as such, there are numerous points where fibril properties can be regulated. Fibril assembly may be modified through the association of different fibrillar collagens to form heterotypic fibrils (Keene et al., 1987, Birk et al., 1988, Mendler, 1989, Linsenmayer et al., 1990, Birk and Linsenmayer, 1994) or by the addition of fibril-associated collagens to fibrils (Mayne and Brewton, 1993, Young et al., 2000). Alternative splicing of collagens also occurs in a tissue-specific manner and confers different properties to fibrils (Sandell et al., 1991, Tsumaki and Kimura, 1995, Oxford et al., 1995). The formation of collagen-proteoglycan heteropolymers also is important in regulation of fibrillogenesis (Scott, 1988, Vogel, 1994, Birk et al., 1995, Danielson et al., 1997, Chakravarti et al., 1998, Svensson et al., 1999, Iozzo, 1999).

Section snippets

Type V collagen

Type V collagen is a quantitatively minor fibrillar collagen present in tissues where type I collagen is expressed. This collagen type can form very small diameter fibrils, where type V collagen triple helical epitopes are exposed, adjacent to cells or basement membranes (Modesti et al., 1984, Gordon et al., 1994). However, the best understood form of this collagen, that has been studied extensively in the corneal stroma, is found in striated fibrils where NH2 epitopes are exposed, and triple

Heterotypic fibrils

Type V collagen is enriched in the cornea relative to other tissues and plays a central role in the regulation of collagen fibril diameter. Evidence for heterotypic fibrils, composed of two different fibrillar collagen types, came initially from studies of type I/V interactions in the mature corneal stroma. The structural similarities of the fibrillar collagen molecules would allow them to co-assemble while their differences alter molecular interactions and regulate assembly steps or influence

NH2-terminal domain of type V collagen

To refine the understanding of how type I and type V collagen co-assemble, the non-collagenous, NH2-terminal domain of type V collagen was studied in the context of fibril structure (Linsenmayer et al., 1993, Birk and Linsenmayer, 1994). An antisera against the NH2-terminal portion of the type V molecule was used to localize this domain. Immunofluorescence localized the NH2 domain of type V collagen throughout the stroma without the prior disruption of fibril structure (Fig. 3). Immunoelectron

Structure of the NH2-terminal domain of type V collagen

The structure of the NH2-terminal domain of type V collagen was studied using rotary shadowing and electron microscopy of the native molecule (Fig. 5A and B). In rotary shadowed preparations, the NH2-terminal domain of the native type V molecule is a multi-domain structure. It consists of a kink, followed by a short rod, terminating in a globular domain. It is ∼17 nm long, a size that fits well with previous determinations (Silver and Birk, 1984, Broek et al., 1985). The amino acid sequence of

Type V collagen regulates diameter

Regulation of fibril diameter by type I/V collagen interactions was demonstrated using an in vitro self-assembly assay (Adachi and Hayashi, 1986, Birk et al., 1990a). Collagen types I and V interact in vitro as heterotypic fibrils and have the same characteristics as those seen in vivo with respect to the masking of the type V collagen helical epitopes. This interaction is at least partially responsible for the control of collagen fibril diameter, and the NH2 domain of the type V collagen

Reduction of type V collagen in situ alters fibril diameter

A dominant-negative strategy was used to reduce the levels of type V collagen. Expression of a truncated α1(V) chain that possessed a complete carboxyl terminus resulted in assembly of hybrid molecules composed of both mutant and endogenous α chains. These hybrids were unstable and were targeted to the intracellular degradation pathway. The reduction in type V collagen was inversely related to fibril diameter in corneal fibroblasts (Marchant et al., 1996).

A replication-defective retrovirus

Heterotypic fibril structure and regulation of initial assembly

The data demonstrate that type V collagen levels play a key role in corneal fibril diameter regulation during the initial assembly of the fibrils. A model for the arrangement of type I/V collagen fibrils is presented in Fig. 11A. In this model the type I and type V molecules are arranged parallel to one another. This requires that the entire triple-helical domain of all the type V collagen molecule be buried within the fibril, and that type I collagen molecules be present along the fibril

Non-corneal type V collagen

Transgenic mutations encompassing the N-telopeptide and propeptidase cleavage site were made in the α2(V) chain (Andrikopoulos et al., 1995). This generates an α2(V) chain where the NH2-terminal propeptide is not cleaved. This would prevent the formation of the ‘hinge’ region that allows the aminopropeptide to project onto the fibril surface (Linsenmayer et al., 1993). Therefore, the ‘hingeless’ molecules are unable to participate in fibrillogenesis. The transgenic mice have numerous connective

Other heterotypic fibrils

Types XI and II collagen co-assemble as heterotypic fibrils in cartilage (Mendler, 1989, Petit et al., 1993) and loss of function mutations in the α1(XI) chain lead to the assembly of collagen fibrils with abnormally large diameters (Li et al., 1995). In addition, mutations that overexpress type II collagen result in a similarly altered XI:II ratio and also drive the assembly of large fibrils (Garofalo et al., 1993). Although it is likely that the α1(V) and α1(XI) chains have comparable

Fibril growth

Collagen fibrillogenesis is a multi-step process. The first step is the assembly of short, small diameter fibril intermediates that have been termed fibril segments (Birk et al., 1989, Birk et al., 1990b, Birk et al., 1995, Birk et al., 1997, Kadler et al., 1996). These immature fibril intermediates form by assembly of procollagen/collagen molecules. This early step in fibrillogenesis is regulated by heterotypic interactions such as the type I/V interactions described in the cornea. We have

Corneal collagen fibril intermediates/segments

Heterotypic assembly in the corneal stroma yields short, immature fibrils (fibril segments). The structure of the early fibril intermediates was analyzed. All immature fibrils demonstrated an asymmetry (Birk et al., 1989, Birk et al., 1990b). Fibril segments had an α end with a long taper and a β end with a short taper (Fig. 12). The lengths of isolated segments were determined for the cornea and the mean was approximately 39.7 μm (Birk et al., 1996). A population of fibril segments in the

Conclusions

The role of corneal type V collagen in regulating the initial stage of fibril assembly is well defined. The mechanism is not unique to the corneal stroma. Rather, heterotypic fibrils containing a quantitatively minor fibrillar collagen, retaining an amino-terminal domain, appear to be a general mechanism regulating the critical assembly step in a variety of rapidly forming tissues. The function of type V collagen in tissues such as skin, bone and tendon where it represents a very small fraction

Acknowledgements

The following people are gratefully acknowledged for their contributions to the work carried out in the author's laboratory: Kathleen Doane, Jeffrey Marchant, Jacqueline Shea McLaughlin, Joanne Babiarz, Rita Hahn and Emanuel Zycband. I would also like to acknowledge productive collaborations with Tom Linsenmayer, John Fitch and Lisa Fessler. The expert technical assistance of Marguarita Schmid in preparation of the figures is appreciated. The work from the authors laboratory was supported by

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