A cysteine-based molecular code informs collagen C-propeptide assembly

Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen’s C-propeptide domain is a key factor g...

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Bibliographic Details
Main Authors: DiChiara, Andrew Stephen, Li, Rasia C., Suen, Patreece H., Hosseini, Azade S., Taylor, Rebecca J., Weickhardt, Alexander F., Malhotra, Diya, Shoulders, Matthew D.
Other Authors: Massachusetts Institute of Technology. Department of Chemistry
Format: Article
Language:English
Published: Springer Science and Business Media LLC 2020
Online Access:https://hdl.handle.net/1721.1/125561
Description
Summary:Fundamental questions regarding collagen biosynthesis, especially with respect to the molecular origins of homotrimeric versus heterotrimeric assembly, remain unanswered. Here, we demonstrate that the presence or absence of a single cysteine in type-I collagen’s C-propeptide domain is a key factor governing the ability of a given collagen polypeptide to stably homotrimerize. We also identify a critical role for Ca2+ in non-covalent collagen C-propeptide trimerization, thereby priming the protein for disulfide-mediated covalent immortalization. The resulting cysteine-based code for stable assembly provides a molecular model that can be used to predict, a priori, the identity of not just collagen homotrimers, but also naturally occurring 2:1 and 1:1:1 heterotrimers. Moreover, the code applies across all of the sequence-diverse fibrillar collagens. These results provide new insight into how evolution leverages disulfide networks to fine-tune protein assembly, and will inform the ongoing development of designer proteins that assemble into specific oligomeric forms.