What Connects Rat Tails to Cancer and Heart Disease?

Collagen is the main (and most abundant) protein in all mammalian connective tissues, including those of the heart, lungs, skin, and tendons. It is also the primary protein in bones and teeth. Bodily malfunctions involving this protein can lead to heart disease and cancer. We know a good deal about how collagen is produced in the body, how it regenerates, and about its physiological structure. But because the collagen protein is so large and insoluble, solving its three-dimensional molecular structure has long been regarded as an impossible, but important, problem. Now, innovative synchrotron x-ray research techniques have yielded new information on the molecular structure of collagen. Because this ubiquitous protein is involved in cancer and heart disease, the data obtained in this study may help in the fight against these deadly ailments.

By adapting methods commonly used for studying much smaller and simpler proteins, researchers from the Illinois Institute of Technology, the Rosalind Franklin University of Medicine and Science, the University of Stirling, and Cardiff University, using the Bio-CAT, SBC-CAT, and SER-CAT beamlines at the APS, have successfully determined the molecular structure of collagen while it is still intact and undisturbed within whole tendons removed from rat tails.

The researchers first used standard fiber diffraction to obtain the diffraction data from whole rat-tail tendons, the source tissue for their experiments. Fiber diffraction patterns are hard to analyze because they are what one would result from capturing dozens of patterns from a single crystal rotated through 360 degrees and superimposing them on top of each other to make one image. The authors devised a custom algorithm to allow untangling the overlapping diffraction spots so that the intensities could be used to solve the structure via “multiple isomorphous replacement” using some of the standard tools used for macromolecular crystallography. The high-quality fiber diffraction data, enabled by the high brilliance of the APS x-ray beams, were crucial to the success of this procedure.

This knowledge may provide clues to key biological processes, such as how normal fine fibrils present in collagen fibers develop and how tissue remodeling occurs, which in turn could yield new insights into inhibiting metastasis of cancer and reversing the effects of heart disease. This represents a scientific breakthrough in understanding the molecular structure of connective tissue in mammals and a significant advance in the technical abilities needed for the study of fibrous proteins in general.

Contact: Joseph Orgel, orgel@iit.edu

See: Joseph P.R.O. Orgel, Thomas C. Irving, Andrew Miller, and Tim J. Wess, “The micro-fibrillar structure of type I collagen in situ,” Proc. Natl. Acad. Sci. USA, 103, 9001 (2006) DOI/10.1073/pnas.0502718103

This work was supported by the American Heart Association Greater Midwest affiliate (#0435339Z), J.P.R.O.O. The BBSRC provided support for T.J.W. (#BBS/B/09643), and A.M acknowledges support from a Leverhulme Emeritus Research Fellowship. BioCAT is a NIH-supported Research Center (RR08630).

Use of the Advanced Photon Source was supported by the U. S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38.

Argonne National Laboratory is a U.S. Department of Energy laboratory managed by The University of Chicago





Photo: Collagen molecule.

The non-helical, folded C-terminal end of the collagen molecule (top) is shown as a red C-alpha trace extending from the triple helical region (below). The electron density of neighboring collagen molecules can be seen along side the chain traced segment.