The expanded collagen VI family: new chains and new questions

Abstract

Collagen VI is a component of the extracellular matrix of almost all connective tissues, including cartilage, bone, tendon, muscles and cornea, where it forms abundant and structurally unique microfibrils organized into different suprastructural assemblies. The precise role of collagen VI is not clearly defined although it is most abundant in the interstitial matrix of tissues and often found in close association with basement membranes. Three genetically distinct collagen VI chains, α1(VI), α2(VI) and α3(VI), encoded by the COL6A1. COL6A2 and COL6A3 genes, were first described more than 20 years ago. Their molecular assembly and role in congenital muscular dystrophy has been broadly characterized. In 2008, three additional collagen VI genes arrayed in tandem at a single gene locus on chromosome 3q in humans, and chromosome 9 in mice, were described. Following the naming scheme for collagens the new genes were designated COL6A4. COL6A5 and COL6A6 encoding the α4(VI), α5(VI) and α6(VI) chains, respectively. This review will focus on the current state of knowledge of the three new chains.

Figure 1

The collagen VI gene locus is disrupted in a subset of primate species. (A) Schematic showing the organization of the collagen VI gene locus in several ape (orangutan, gibbon), old world monkey (rhesus monkey, baboon), new world monkey (squirrel monkey, marmoset), lemur (mouse lemur) and loris (bushbaby) genomes. The p arm (to the left of the centromere, in red), q arm (to the right of the centromere, in blue) and centromere (filled black circle) of the chromosome containing the collagen VI gene locus is shown. Below the chromosome, the Col6a4, Col6a5 and Col6a6 genes are represented by arrowed boxes to indicate the orientation of each gene. All genes flanking the collagen VI gene locus are conserved in all these primate species (orange and yellow boxes flanking collagen VI gene cluster). Note that this gene organization is the ancestral state because it is conserved in all vertebrate species that genome data is available for including mouse, rat, dog, platypus and lizard. (B) The same locus in the human, chimpanzee and gorilla genomes. In these species the locus has been disrupted by an evolutionary pericentric inversion with one breakpoint located within the COL6A4 gene and the other breakpoint in the p arm of chromosome 3 (in humans) represented by arrows in (A). In human, chimpanzee and gorilla, genomic DNA telomeric to the inversion remains contiguous with COL6A5 and COL6A6. The block of genomic DNA on the centromeric side of the break has been translocated to the p arm of chromosome 3. The disrupted halves of the COL6A4 gene are presumably non-functional and have been designated COL6A4P1 and P2.

Figure 2

Domain structures of the six collagen VI chains. Representation of the human α1(VI), α2(VI), α3(VI), α5(VI) and α6(VI), and mouse α4(VI) collagen chains. Each chain is drawn to the same relative scale to reflect the differences in size between the six chains. Multiple N- and C-terminal von Willebrand factor A-like (VWA) domains (blue circles) are numbered consistent with previous reports (8,15). The fibronectin type-III repeat unique to α3(VI) (red square labelled C4), Kunitz and partial Kunitz domains of α3(VI) and α4(VI) respectively (orange hexagon labelled C5 and partial hexagon) and a conserved region unique to the α3, α4, α5 and α6 chains (purple oval shapes) are shown. The position of the triple helical cysteine (Cys) residue important for stabilizing assembly intermediates is shown in all six chains. These are located at amino acid 89 from the start of the triple helix domain in α1(VI) and α2(VI) and closer to the start of the triple helix at amino acid 50 in the α4, α5 and α6(VI) chains. Putative N-linked glycosylation sites were determined using NetNGlyc 1.0 server (http://www.cbs.dtu.dk/services/NetNGlyc/).