Collagen is an important protein that helps build the tissues of humans and animals. It is very strong because it is made of three protein strands twisted tightly together like a rope. Because of this sturdy structure, ordinary protein-cutting enzymes usually cannot break it down.
Some disease-causing bacteria, however, can destroy this tough collagen by releasing a collagen-digesting enzyme called bacterial collagenase. This allows the bacteria to damage tissue and spread infection quickly. At the same time, this enzyme is also useful in medicine because of its strong ability to dismantle the collagen scaffold surrounding cells.
For example, it is used in pancreatic islet transplantation for diabetes treatment, when insulin-producing cells from a pancreas are introduced into the liver, to isolate target cells from donor tissues. It is also used therapeutically for fibrotic conditions such as Dupuytren’s contracture, in which collagen-rich cords form in the hand and lead to finger contraction. Collagenase can be useful in breaking down the excess collagen, increasing mobility.
An international research team, including the University of Arkansas and several from Japanese universities (Osaka University, Okayama University, Ehime University of Health Sciences, Waseda University) has now revealed in Nature Communications how this bacterial enzyme continuously breaks down collagen. The researchers analyzed the structure and dynamics of the ColH enzyme at the atomic level and elucidated the mechanism underlying its highly efficient, processive collagen cleavage. These findings are expected to enable the rational design and improvement of recombinant enzymes and to support a wide range of applications in transplantation and regenerative medicine.
The U of A team was led by Josh Sakon, a professor of biochemistry who has been collaborating with Osamu Matsushita of Okayama University for more than 30 years. In the 1990s, Matsushita and colleagues identified and named two collagenase genes (colG and colH). Based on these discoveries, recombinant enzymes were developed and have since been commercialized by several biotechnology companies. However, the mechanism by which these enzymes efficiently degrade collagen has remained unclear.
Sakon thinks that understanding this mechanism should lead to better therapeutics. Some cancer cells, he noted, can be covered in thick layers of collagen like a protein shield. As a potential therapeutic, collagenase could be used to “strip off the cancer’s guard shield so that the cells will be more vulnerable to the attack of chemotherapy drugs.”
Collagen Versus Collagenase
Triple-helical collagen evolved roughly a billion years ago and played a key role in allowing cells to stick together and form multicellular organisms. The tightly wound triple-helix structure protects the protein’s peptide bonds from being easily cut by enzymes. It took bacteria hundreds of millions of years to evolve enzymes capable of breaking down this structure.
The enzyme has a shape that looks somewhat like a donut. Part of this ring can open and close, allowing the spiral-shaped collagen molecule to enter the inside of the enzyme. The researchers call this the dynamic form.
Next, the enzyme removes water molecules around the collagen and loosens its tightly wound structure. It then holds the three collagen strands in separate positions inside the ring. The researchers call this the ratchet form.
At this point, one of the three strands is pulled out into a small loop and positioned in the enzyme’s active site—the region where the chemical reaction occurs. The enzyme pulls the strand forward before cutting, allowing it to advance stepwise along the collagen. As it advances, the remaining two strands act like rails that guide the enzyme along the collagen molecule.
After one cut is made, the enzyme appears to return to the dynamic form, shift to the next position, and begin the next cutting cycle. In other words, this bacterial collagenase seems to work like a ratchet: once it moves forward, it does not easily slip backward. By repeating this process, it travels in one direction along the collagen molecule and cuts it apart step by step.
Sakon commented that “just as martial arts such as judo and aikido use an opponent’s force to gain advantage, this study reveals that bacterial collagenase exploits the intrinsic structure of collagen itself to drive its degradation.”
Sakon also noted that in cases of gas gangrene, which is contracted from bacteria living in soil, the enzyme can destroy up to an inch of tissue an hour.
This mechanism is completely different from the way collagen is broken down by collagen-digesting enzymes in humans and animals. The finding is interesting from an evolutionary point of view and may also help future advances in transplantation medicine and the treatment of infectious diseases.
Additional authors included Hiroya Oki, Katsuki Takebe, Adjoa Bonsu, Kazunori Fujii, Ryo Masuda, Nicholas Henderson, Takehiko Mima, Takaki Koide, Mahmoud Moradi and Kazuki Kawahara. Bonsu is a former Ph.D. student in chemistry and biochemistry at the U of A while Henderson is a current Ph.D. student in the same department. Moradi is a professor of physical chemistry and biochemistry at the U of A.
Nature Communications
Imaging analysis
Cells
Bacterial collagenase harnesses collagen geometry for processive cleavage
2-Apr-2026
The authors declare no competing interests.