Unexpected discovery of collagen structures indicates greater diversity than previously believed

Collagen, the body’s most abundant protein, has long been considered a predictable structural component of tissue. However, a new study led by Jeffrey Hartgarin and Tracy Yu of Rice University, in collaboration with Mark Kreuzberger and Edward Egelman of the University of Virginia (UVA) is likely to reconstruct biomedical research. Reveals unexpected confirmation of certain collagen structures.

Researchers used advanced ultra-low electron microscopy (Cryo-EM) to determine the atomic structure of packed collagen assemblies that deviate from the traditionally accepted right-handed super-covered torsion . The study, published February 3rd in ACS Central Science, suggests that the structural diversity of collagen may be greater than previously believed.

“This work fundamentally changes the way we think about collagen,” says Hartgerink, a professor of chemistry and bioengineering. “For decades, we have assumed that collagen triple helixes always follow a strict structural paradigm. Our findings show that collagen assemblies can employ a wider conformation than previously thought. It’s there.”

Introducing the new three-dimensional structure of collagen

To explore collagen assemblies at the atomic level, the researchers designed a system of self-assembled peptides based on the collagen-like region of C1Q, a key immune protein. They then used Cryo-EM, a technique that allows scientists to analyze the structure of assembled peptides, to allow scientists to visualize biomolecules in unprecedented detail. The resulting model revealed a departure from the standard right-handed, ultra-helical twist.

This unexpected conformation allows for unique molecular interactions, such as hydroxyproline stacking between adjacent helixes and the formation of symmetrical hydrophobic cavity. These features suggest that collagen assemblies may be much more structurally diverse than previously thought.

“The lack of a superhelical twist allows for molecular interactions that were not previously seen in collagen,” said Yu, a former graduate student at Hartgerink, who is now a postdoctoral researcher at the University of Washington.

Kreutzberger, the first author of the study, said the findings actually questioned previous beliefs. “It challenges longstanding doctrines regarding the structure of collagen and opens the door to reexamining its biological role,” Kleutzberger said.

The importance of medicine and biomaterials

The implications of this discovery may extend beyond basic biology. Collagen is not just a structural protein, but plays an essential role in cell signaling, immune function and tissue repair.

A deeper understanding of the structural variability of collagen can unlock new insights into diseases where collagen assembly is impaired, such as Ehlers-Danlos syndrome, fibrosis, and certain cancers.

Furthermore, this study forms the basis for innovation in biomaterials and regenerative medicine. By leveraging the unique structural properties of this newly identified collagen conformation, scientists were able to design new materials for wound healing, tissue engineering and drug delivery.

Cryo-Em’s breakthrough in structural biology

Despite the ubiquity of collagen in human biology, studying higher order structures at high resolution was a challenge. While traditional techniques such as X-ray crystallography and fiber diffraction provide valuable insights, complex assemblies have not been able to capture collagen packaging. However, Cryo-Em overcomes these limitations, allowing the researchers to visualize the complex architecture of collagen with new details.

“Our research highlights the importance of improving our understanding of collagen and reexamining other biological structures that were previously thought to have been well understood,” he said. Egerman, who studied the authors, stated:

Co-authors of this study include Michael Purdy of UVA. Thi Bui and Maria Hancu of Rice’s Ministry of Chemistry; Thomas Osinski of the University of Southern California; Peter Cusson of Georgia Tech.