Collagen, known for its structural role in tissues and also for its participation in the regulation of homeostatic and
pathological processes in mammals, is assembled from triple helices that can be either homotrimers or heterotrimers. High resolution structural information for natural
collagens has been difficult to obtain because of their size and the heterogeneity of their native environment. For this reason,
peptides that self-assemble into
collagen-like triple helices are used to gain insight into the structure, stability, and biochemistry of this important
protein family. Although many of the most common
collagens in humans are heterotrimers, almost all studies of
collagen helices have been on homotrimers. Here we report the first structure of a
collagen heterotrimer. Our structure, obtained by
solution NMR, highlights the role of electrostatic interactions as stabilizing factors within the triple helical folding motif. This addresses an issue that has been actively researched because of the predominance of charged residues in the
collagen family. We also find that it is possible to selectively form a
collagen heterotrimer with a well defined composition and register of the
peptide chains within the helix, based on information encoded solely in the collagenous domain. Globular domains are implicated in determining the composition of several
collagen types, but it is unclear what their role in controlling register may be. We show that is possible to design
peptides that not only selectively choose a composition but also a specific register without the assistance of other
protein constructs. This mechanism may be used in nature as well.