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Toughing It Out in Membranes

The formation of crosslinks in the triple-helical structure of collagen is crucial to its function. In the case of collagen IV, which provides structural integrity to the basement membrane of animal tissues, the chemical nature of the crosslinks has been difficult to pin down. Vanacore et al. (p. 1230) report a combination of high-resolution mass spectrometric and nuclear magnetic resonance studies that establish the crosslink between hydroxylysine-211 and methionine-93 is a sulfimine group (-S=N-). This type of bond appears to have evolved to withstand mechanical stress as animals evolved into more structurally complex organisms.

Abstract

Collagen IV networks are ancient proteins of basement membranes that underlie epithelia in metazoa from sponge to human. The networks provide structural integrity to tissues and serve as ligands for integrin cell-surface receptors. They are assembled by oligomerization of triple-helical protomers and are covalently crosslinked, a key reinforcement that stabilizes networks. We used Fourier-transform ion cyclotron resonance mass spectrometry and nuclear magnetic resonance spectroscopy to show that a sulfilimine bond (-S=N-) crosslinks hydroxylysine-211 and methionine-93 of adjoining protomers, a bond not previously found in biomolecules. This bond, the nitrogen analog of a sulfoxide, appears to have arisen at the divergence of sponge and cnidaria, an adaptation of the extracellular matrix in response to mechanical stress in metazoan evolution.

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Information

Published In

Science
Volume 325 | Issue 5945
4 September 2009

Submission history

Received: 26 May 2009
Accepted: 13 July 2009
Published in print: 4 September 2009

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Acknowledgments

We thank D. Liebler for facilitating the initial contact with T. D. Veenstra from SAIC-Frederick, Incorporated, and C. Bolm (Aachen University, Germany) for helpful discussions. The technical assistance of P. Todd and M. Rafi is greatly appreciated. We would also like to thank S. Hill and H. McDonald, from the Proteomics Laboratory at the Mass Spectrometry Research Center of Vanderbilt University, for their assistance with the Orbitrap-LTQ (Therme Electron, San Jose, CA) instrument. This work was supported in part by NIH grants DK065123 and DK18381 (to B.G.H.), DC007416 (C.R.S.), and GM059380 (P.E.D.); the W. M. Keck Foundation (K.B.S.); and the Skaggs Institute for Chemical Biology (K.B.S.). R.V. and B.G.H. have filed a provisional patent (1 June 2009) on the potential enzyme system that catalyses the sulfilimine bond formation and that may be involved in pathophysiological processes.

Authors

Affiliations

Roberto Vanacore* [email protected]
Division of Nephrology, Department of Medicine and Center for Matrix Biology, Vanderbilt University, Nashville, TN 37232, USA.
Amy-Joan L. Ham
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Markus Voehler
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Charles R. Sanders
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Thomas P. Conrads
Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Incorporated, National Cancer Institute, Frederick, MD 21702, USA.
Timothy D. Veenstra
Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Incorporated, National Cancer Institute, Frederick, MD 21702, USA.
K. Barry Sharpless
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Philip E. Dawson
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Billy G. Hudson* [email protected]
Division of Nephrology, Department of Medicine and Center for Matrix Biology, Vanderbilt University, Nashville, TN 37232, USA.
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
Department of Pathology, Vanderbilt University, Nashville, TN 37232, USA.

Notes

Present address: Jim Ayers Institute for Precancer Detection and Diagnosis, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Present address: Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
*
To whom correspondence should be addressed. E-mail: [email protected] (R.V.); [email protected] (B.G.H.)

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