Molecular motor implicated in tissue remodeling

Sept. 30, 2004 -- A well-known enzyme present in the skin and other tissues turns out to be a molecule-sized motor that extracts its fuel from the road it runs on, according to researchers at Washington University School of Medicine in St. Louis. Their discovery appears in the Oct. 1 issue of Science.

The enzyme, MMP-1, is a member of a group of enzymes that breaks down collagen, a fibrous substance that constitutes the foundation of the extracellular matrix that supports the cells in the body's tissues.

"By digesting collagen, enzymes such as MMP-1 initiate tissue remodeling, which can have a variety of purposes from organ development to tissue repair to metastatic invasion of tumors," says senior author Gregory Goldberg, Ph.D., professor of dermatology and of biochemistry and molecular biophysics. "Because they participate in all basic tissue metabolism, we want to understand how they function."

Goldberg and his colleagues Savees Saffarian, Ivan Collier, Barry Marmer and Elliot Elson found that MMP-1 operates as a molecular motor—a molecule that converts chemical energy into motion. "This is the only extracellular motor known," says Elson, Ph.D., coauthor and professor of biochemistry and molecular biophysics.

The research team discovered that MMP-1 moves along a collagen filament with a net unidirectional motion. One-way motion indicates that energy is being utilized, so the team looked for an energy source.

While most molecules that act as motors are inside cells and get their energy from a ubiquitous high-energy molecule called ATP, the team found that MMP-1 gets its energy by breaking the molecular bonds in the collagen filament it is attached to.

"In fact," Goldberg says, "with our model, a whole new principle emerges in which molecular motors in the extracellular matrix operate by extracting energy from the very track they move upon."

The researchers propose that the molecular motor contributes to restructuring the extracellular support matrix during tissue growth and development or wound repair or even during cancerous invasion of tissues. Because MMP-1 moves directionally, it can serve as a clutch, assisting cell locomotion along networks of collagen in tissues. Further, motion along the precisely aligned collagen filaments directs the proper development of individual tissue types.

The model of MMP-1 action revealed by Goldberg and his colleagues might help explain how the enzymes that digest collagen serve constructive purposes. "The enzymes aren't loose and disorganized where they would just end up destroying the matrix," Goldberg states. "By mechanisms that we are exploring further, they create a relation between cells and the structures in the matrix. It's a very elegant system."

Saffarian S, Collier IE, Marmer BL, Elson EL, Goldberg G. Interstitial collagenase is a Brownian ratchet driven by proteolysis of collagen. Science, Oct. 1, 2004.

Funding from the National Institutes of Health and a Washington University-Pfizer Inc. agreement supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.