Figure 6.

Schematic diagram showing the effects of two different internal deletions on collagen VI assembly. A, Intracellular events. Normally (left), the α1(VI), α2(VI), and α3(VI) collagen chains presumably fold from the C-terminal end into a triple-helical monomer. Two key cysteine residues (vertical lines) in the N-terminal portion of the triple helix are critical for subsequent supramolecular assembly. Dimers are formed by the staggered antiparallel association of monomers with the N-terminal globular domains protruding at both ends. The outer cysteines contributed by either the α1(VI) or α2(VI) collagen chains are important for the dimer assembly. The dimers associate laterally into tetramers, which are stabilized by the outer cysteines contributed by the α3(VI) collagen chain. In UC-1 (middle) and UC-4 (right), equal amounts of normal and mutant (gray) α1(VI) collagen chains assemble into equal amounts of normal and mutant monomers. Because the cysteines critical for dimer and tetramer formation are preserved in UC-1, both normal and mutant monomers can assemble into dimers and tetramers in any combination. Thus, only 1/4 of the dimers and 1/16 of the tetramers are entirely composed of normal chains, whereas 15/16 of the tetramers contain a mixture of normal and mutant chains (gray striped lines). The deletion in UC-4 removes the cysteine in the triple-helical domain of the α1(VI) collagen chain, which prevents the abnormal monomers from assembling into dimers. Therefore, only normal tetramers are formed and secreted. The mutant chain in UC-4 may interfere with the assembly of the normal dimers, resulting in the formation and secretion of normal tetramers at a level ⩽1/2 that of the control. B, Extracellular event. Normally, tetramers are secreted and associated end-to-end into double-beaded microfibrils (top). The microfibrillar assembly involves interactions of the N- and C-globular domains and triple-helical domain. The deletion in UC-1 is located very close to the N-terminal end of the triple-helical domain (broken thick lines). Presumably, the triple helix in the mutant monomer is shortened because the normal α2(VI) and α3(VI) collagen chains are looped out at the region corresponding to the deletion (bottom). As a result, the mutant tetramers cannot properly align with normal tetramers to form the double-beaded structure. Because the majority of the secreted tetramers are abnormal, long microfibrils cannot be assembled.