Cryo-EM Uncovers Hidden Complexity in Collagen Structure

Collagen, the body’s most abundant protein, has long been considered a predictable structural component of tissues. However, a recent study by Jeffrey Hartgerink and Tracy Yu of Rice University, along with Mark Kreutzberger and Edward Egelman of the University of Virginia (UVA), challenges that assumption. Their research uncovers an unexpected collagen structure that could shift the course of biomedical science.

Using advanced cryo-electron microscopy (cryo-EM), the team identified a packed collagen assembly with a structural conformation that deviates from the traditionally recognized right-handed superhelical twist.

Published in ACS Central Science, the study suggests that collagen’s structural diversity is greater than previously thought.

“This work fundamentally changes how we think about collagen. For decades, we assumed that collagen triple helices followed a strict structural paradigm. Our findings show that collagen assemblies can adopt a wider range of conformations than we ever imagined.”

Jeffrey Hartgerink, Professor, Rice University

Unveiling a New Collagen Conformation

To explore collagen at an atomic level, the researchers designed a system of self-assembling peptides inspired by the collagen-like region of C1q, a key immune protein. Cryo-EM, which allows scientists to visualize biomolecules with unprecedented clarity, revealed a surprising structural deviation from the canonical right-handed superhelical twist.

This newly identified conformation enables molecular interactions never before observed in collagen, such as hydroxyproline stacking between adjacent helices and the formation of a symmetrical hydrophobic cavity. These unique features suggest that collagenous assemblies may be far more structurally versatile than previously recognized.

“The absence of the superhelical twist allows for molecular interactions not seen before in collagen,” 

Tracy Yu, a former graduate student in Hartgerink’s lab and now a postdoctoral researcher at the University of Washington.

Mark Kreutzberger, the study’s first author, highlighted the significance of the discovery:

“It challenges the long-held dogma about collagen structure and opens the door to re-examining its biological roles.”

Implications for Medicine and Biomaterials

Collagen is not just a structural protein—it plays crucial roles in cell signaling, immune function, and tissue repair. Understanding its structural variability could offer new insights into diseases linked to collagen misassembly, such as Ehlers-Danlos syndrome, fibrosis, and certain cancers.

Beyond fundamental biology, this research lays the groundwork for innovations in biomaterials and regenerative medicine. By harnessing the unique properties of this newly identified collagen conformation, scientists may develop advanced materials for wound healing, tissue engineering, and drug delivery.

Cryo-EM: A Game Changer in Structural Biology

Despite collagen’s ubiquity in the body, studying its higher-order structures at high resolution has been a long-standing challenge. Traditional techniques like X-ray crystallography and fiber diffraction provided valuable insights but struggled to capture the complexity of collagen packing in intricate assemblies.

Cryo-EM has changed that. This breakthrough technology allowed the researchers to visualize collagen’s architecture with unprecedented detail, refining our understanding of the protein and encouraging a fresh look at other biological structures once thought to be well understood.

“Our research not only deepens our understanding of collagen but also underscores the importance of re-examining other biological structures that we may have taken for granted.”

Edward Egelman, Study Co-Corresponding Author, University of Virginia

This discovery opens new avenues for biomedical research, pushing scientists to rethink the complexity of collagen and its potential applications. As research progresses, it could lead to breakthroughs in disease treatment, biomaterial development, and regenerative medicine.