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

• Main Authors: DiChiara, Andrew Stephen (Author), Li, Rasia C. (Author), Suen, Patreece H. (Author), Hosseini, Azade S. (Author), Taylor, Rebecca J. (Author), Weickhardt, Alexander F. (Author), Malhotra, Diya (Author), Shoulders, Matthew D. (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Chemistry (Contributor), McGovern Institute for Brain Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Springer Science and Business Media LLC, 2020-05-28T17:31:58Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Science Foundation (U.S.) (Grant NSF-0070319)
National Science Foundation (U.S.). Center for Science of Information (Grant P30-ES002109)
National Institutes of Health (U.S.) (Grant R03AR067503)
National Institutes of Health (U.S.) (Grant 1R01AR071443)
National Institutes of Health (U.S.). Ruth Kirschstein Predoctoral Fellowship (1F31AR067615)