Collagen, recognized as the most abundant protein in the body, has traditionally been understood as a straightforward structural element of various tissues. Nevertheless, a recent study spearheaded by Jeffrey Hartgerink and Tracy Yu from Rice University, alongside collaborators Mark Kreutzberger and Edward Egelman from the University of Virginia (UVA), challenges this established view by uncovering an unforeseen confirmation in the structure of collagen that may revolutionize biomedical research.
The research team utilized cutting-edge cryo-electron microscopy (cryo-EM) to investigate the atomic structure of a dense collagen assembly that diverges from the previously accepted right-handed superhelical twist. Published on February 3 in ACS Central Science, this study indicates that collagen’s structural diversity is likely greater than what was once thought.
“This study fundamentally alters our understanding of collagen,” stated Hartgerink, a professor in chemistry and bioengineering. “For many years, we believed that collagen triple helices adhered to a rigid structural framework. Our results demonstrate that collagen assemblies can take on a broader variety of shapes than was previously considered.”
Revealing a new formation of collagen
To delve into collagen assembly at an atomic scale, the research group engineered a system of self-assembling peptides derived from the collagen-like area of C1q, a vital immune protein. Using cryo-EM, a technique that permits scientists to observe biomolecules with remarkable clarity, they scrutinized the structure of the assembled peptides. The analysis unveiled a departure from the typical right-handed superhelical configuration.
This surprising conformation facilitates distinctive molecular interactions, such as hydroxyproline stacking between nearby helices, creating a symmetrical hydrophobic cavity. These characteristics imply that collagenous assemblies may possess far greater structural variety than was previously acknowledged.
“The lack of the superhelical twist enables molecular interactions that have not been observed in collagen before,” remarked Yu, a previous graduate student under Hartgerink who is now a postdoctoral researcher at the University of Washington.
Kreutzberger, the study’s lead author, noted that this finding indeed challenges prior assumptions. “It undermines the long-standing beliefs regarding collagen structure and invites a reevaluation of its biological functions,” Kreutzberger explained.
Relevance for medicine and biomaterials
The ramifications of this discovery may extend beyond basic biological understanding. Collagen is not solely a structural protein; it is integral to various processes such as cell signaling, immune responses, and tissue healing.
By deepening the comprehension of collagen’s structural variability, researchers could gain valuable insights into conditions where collagen assembly is disrupted, including Ehlers-Danlos syndrome, fibrosis, and specific cancers.
Moreover, this research establishes a foundation for advancements in biomaterials and regenerative medicine. By utilizing the unique structural characteristics of this newly recognized collagen formation, scientists could create innovative materials for applications in wound healing, tissue engineering, and drug delivery.
Cryo-EM’s advancement in structural biology
Even with collagen’s prevalence in human biology, gaining high-resolution insights into its higher-order structures has posed challenges. Conventional methods such as X-ray crystallography and fiber diffraction have provided useful information but failed to adequately depict collagen packing within complex assemblies. Cryo-EM has addressed these challenges, enabling the research team to visualize collagen’s complex architecture in unprecedented detail.
“Our study enhances our comprehension of collagen and emphasizes the necessity to revisit other biological structures previously assumed to be well understood,” Egelman, a co-corresponding author of the study, stated.
Other contributors to the study include Michael Purdy from UVA; Thi Bui and Maria Hancu from the Department of Chemistry at Rice; Tomasz Osinski from the University of Southern California; and Peter Kasson from the Georgia Institute of Technology.
This research was funded by the U.S. National Science Foundation Division of Chemistry, The Robert A. Welch Foundation, and the National Institute of General Medical Sciences.
