Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown
Collagen cleavage, facilitated by collagenases of the matrix metalloproteinase (MMP) family, is crucial for many physiological and pathological processes such as wound healing, tissue remodeling, cancer invasion and organ morphogenesis. Earlier work has shown that mechanical force alters the cleavag...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2016
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| Online Access: | http://hdl.handle.net/1721.1/101438 https://orcid.org/0000-0002-4173-9659 |
| _version_ | 1811093571339550720 |
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| author | Chang, Shu-Wei Flynn, Brendan P. Ruberti, Jeffrey W. Buehler, Markus J |
| author2 | Massachusetts Institute of Technology. Center for Materials Science and Engineering |
| author_facet | Massachusetts Institute of Technology. Center for Materials Science and Engineering Chang, Shu-Wei Flynn, Brendan P. Ruberti, Jeffrey W. Buehler, Markus J |
| author_sort | Chang, Shu-Wei |
| collection | MIT |
| description | Collagen cleavage, facilitated by collagenases of the matrix metalloproteinase (MMP) family, is crucial for many physiological and pathological processes such as wound healing, tissue remodeling, cancer invasion and organ morphogenesis. Earlier work has shown that mechanical force alters the cleavage rate of collagen. However, experimental results yielded conflicting data on whether applying force accelerates or slows down the degradation rate. Here we explain these discrepancies and propose a molecular mechanism by which mechanical force might change the rate of collagen cleavage. We find that a type I collagen heterotrimer is unfolded in its equilibrium state and loses its triple helical structure at the cleavage site without applied force, possibly enhancing enzymatic breakdown as each chain is exposed and can directly undergo hydrolysis. Under application of force, the naturally unfolded region refolds into a triple helical structure, potentially protecting the molecule against enzymatic breakdown. In contrast, a type I collagen homotrimer retains a triple helical structure even without applied force, making it more resistant to enzyme cleavage. In the case of the homotrimer, the application of force may directly lead to molecular unwinding, resulting in a destabilization of the molecule under increased mechanical loading. Our study explains the molecular mechanism by which force may regulate the formation and breakdown of collagenous tissue. |
| first_indexed | 2024-09-23T15:47:13Z |
| format | Article |
| id | mit-1721.1/101438 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:47:13Z |
| publishDate | 2016 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1014382022-10-02T04:06:10Z Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown Chang, Shu-Wei Flynn, Brendan P. Ruberti, Jeffrey W. Buehler, Markus J Massachusetts Institute of Technology. Center for Materials Science and Engineering Massachusetts Institute of Technology. Center for Computational Engineering Massachusetts Institute of Technology. Department of Civil and Environmental Engineering Massachusetts Institute of Technology. Laboratory for Atomistic and Molecular Mechanics Chang, Shu-Wei Buehler, Markus J. Collagen cleavage, facilitated by collagenases of the matrix metalloproteinase (MMP) family, is crucial for many physiological and pathological processes such as wound healing, tissue remodeling, cancer invasion and organ morphogenesis. Earlier work has shown that mechanical force alters the cleavage rate of collagen. However, experimental results yielded conflicting data on whether applying force accelerates or slows down the degradation rate. Here we explain these discrepancies and propose a molecular mechanism by which mechanical force might change the rate of collagen cleavage. We find that a type I collagen heterotrimer is unfolded in its equilibrium state and loses its triple helical structure at the cleavage site without applied force, possibly enhancing enzymatic breakdown as each chain is exposed and can directly undergo hydrolysis. Under application of force, the naturally unfolded region refolds into a triple helical structure, potentially protecting the molecule against enzymatic breakdown. In contrast, a type I collagen homotrimer retains a triple helical structure even without applied force, making it more resistant to enzyme cleavage. In the case of the homotrimer, the application of force may directly lead to molecular unwinding, resulting in a destabilization of the molecule under increased mechanical loading. Our study explains the molecular mechanism by which force may regulate the formation and breakdown of collagenous tissue. National Science Foundation (U.S.) (CAREER CMMI-0642545) National Science Foundation (U.S.). Integrative Graduate Education and Research Traineeship (Nanomedicine Award DGE-0504331) National Institutes of Health (U.S.) (NEIEY0155500) 2016-03-03T17:47:23Z 2016-03-03T17:47:23Z 2012-03 2012-01 Article http://purl.org/eprint/type/JournalArticle 01429612 1878-5905 http://hdl.handle.net/1721.1/101438 Chang, Shu-Wei, Brendan P. Flynn, Jeffrey W. Ruberti, and Markus J. Buehler. “Molecular Mechanism of Force Induced Stabilization of Collagen Against Enzymatic Breakdown.” Biomaterials 33, no. 15 (May 2012): 3852–3859. https://orcid.org/0000-0002-4173-9659 en_US http://dx.doi.org/10.1016/j.biomaterials.2012.02.001 Biomaterials Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Chang, Shu-Wei Flynn, Brendan P. Ruberti, Jeffrey W. Buehler, Markus J Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title | Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title_full | Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title_fullStr | Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title_full_unstemmed | Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title_short | Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| title_sort | molecular mechanism of force induced stabilization of collagen against enzymatic breakdown |
| url | http://hdl.handle.net/1721.1/101438 https://orcid.org/0000-0002-4173-9659 |
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