Type I procollagen heterotrimer assembly is linked to subtle differences in the structures of the pro-alpha l(I) and pro-alpha 2(I)-carboxyl-propeptides

The assembly of the type I procollagen heterotrimer is initiated by an inte raction between the carboxyl propeptides, with triple helix folding proceed ing in the C --> N direction. The pro-alpha 1(I)-C-propeptides can interact with self to form the homotrimer or with pro-alpha 2(I)-C-propeptide to es tablish the heterotrimer. The two propeptides are similar in length and hav e about 65% identity in sequence. Nevertheless, we proposed that difference s in interaction between propeptides might account for the in vivo selectio n of heterotrimer formation rather than homotrimer formation. To test this hypothesis we have determined the probable structures of the human C-propep tides by molecular modeling and energy minimization using Molecular Simulat ions Insight, Discover 95.0/3.0, and Biopolymer programs. The propeptide st ructures were constrained with the two known intrachain disulfide bonds in each case. The two structures were globally similar, with three distinct st ructural domains (G-I, L, G-II) in each case. A few crucial Pro residues an d other sequence differences, however, produced different structures in eac h domain. The different interaction profiles of the three domains may be of crucial importance for heterotrimer selection.