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Assembly and network organization of collagen IV protomers

Assembly and network organization of collagen IV protomers

Protomers create basement-membrane networks with other protomers by uniting two NC1 trimers to form an interface hexamer at the C-terminal and by uniting four triple helical 7S domains at the N-terminal (panel A). A network composed of alpha 3, 4, 5 (type IV) protomers is illustrated, showing end-to-end connections of individual protomer units, supercoiling and looping of the triple helixes, and disulfide cross-links between triple helical domains.[1-4] The structure of the NC1 hexamer is determined by the particular alpha chains that form a triple helical protomer and by the particular canonical protomers that can connect to adjoining protomers (NC1 box). Molecular recognition sequences encoded within NC1 domains govern the selection of partner chains for both protomer and network assembly. The 7S domains also play a key part in determining the specificity, affinity, and geometry of the tetramer formed through the connection of four protomers (7S box).[4-6] Two other networks are composed of pairs of alpha 1, 1, 2(IV) hexamers or alpha 1, 1, 2(IV)–alpha 5, 5, 6(IV) NC1 hexamers.[1-4] The alpha 3, 4, 5 (IV)–alpha 3, 4, 5(IV) network differs from the others in that it has a greater number of disulfide cross-links between triple helical domains, which increases its resistance to proteolysis.[7]

Panel B shows the three-dimensional model of the alpha 3, 4, 5(IV) NC1 hexamer that is depicted in the NC1 box in panel A. The three-dimensional structure and the location of epitopes were determined by computer modeling of the crystal structure of the alpha 1, 1, 2(IV)–alpha 1, 1, 2(IV) hexamer[8] and the apparent quaternary structure of the alpha 3, 4, 5(IV) hexamer.[2] The hexamer is composed of two trimeric caps, each derived from adjacent protomers. Each trimer consists of an alpha 3 monomer (red), an alpha 4 monomer (blue), and an alpha 5 monomer (green). The monomers have a novel tertiary structure with two homologous subdomains, each of which is characterized by beta-sheet motifs. The model depicts the location of the EA (yellow) and EB (gold) regions that encompass two dominant epitopes for Goodpasture antibodies. The epitopes reside in the alpha 3(IV) NC1 domain, near the triple helical junction, and they are partially sequestered by interactions with the alpha 5(IV) and alpha 4(IV) NC1 domains, respectively.
E: epitope; NC1: noncollagenous.
References:
  1. Boutaud A, Borza DB, Bondar O, et al. Type IV collagen of the glomerular basement membrane: Evidence that the chain specificity of network assembly is encoded by the noncollagenous NC1 domains. J Biol Chem 2000; 275:30716.
  2. Borza DB, Bondar O, Todd P, et al. Quaternary organization of the Goodpasture autoantigen, the α3(IV) collagen chain: Sequestration of two cryptic autoepitopes by intraprotomer interactions with the α4 and α5 NC1 domains. J Biol Chem 2002; 277:40075.
  3. Borza DB, Bondar O, Ninomiya Y, et al. The NC1 domain of collagen IV encodes a novel network composed of the alpha 1, alpha 2, alpha 5, and alpha 6 chains in smooth muscle basement membranes. J Biol Chem 2001; 276:28532.
  4. Timpl R, Wiedemann H, van Delden V, et al. A network model for the organization of type IV collagen molecules in basement membranes. Eur J Biochem 1981; 120:203.
  5. Langeveld JP, Noelken ME, Hard K, et al. Bovine glomerular basement membrane: Location and structure of the asparagine-linked oligosaccharide units and their potential role in the assembly of 7 S collagen IV tetramer. J Biol Chem 1991; 266:2622.
  6. Nayak BR, Spiro RG. Localization and structure of the asparagine-linked oligosaccharides of type IV collagen from glomerular basement membrane and lens capsule. J Biol Chem 1991; 266:13978.
  7. Kalluri R, Shield CF, Todd P, et al. Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 1997; 99:2470.
  8. Sundaramoorthy M, Meiyappan M, Todd P, Hudson BG. Crystal structure of NC1 domains: Structural basis for type IV collagen assembly in basement membranes. J Biol Chem 2002; 277:31142.

From: Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport's syndrome, Goodpasture's syndrome, and type IV collagen. N Engl J Med 2003; 348:2543. Copyright © 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

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