Skip to main content Accessibility help
×
Home
Hostname: page-component-684899dbb8-67wsf Total loading time: 0.337 Render date: 2022-05-21T17:06:30.199Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true }

Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen

Published online by Cambridge University Press:  31 January 2011

Maya Srinivasan
Affiliation:
mayas@princeton.edu, Princeton University, Mechanical Engineering, 3633 Frist Center, Princeton, New Jersey, 08544, United States
Sebastien G.M. Uzel
Affiliation:
suzel@MIT.EDU, Massachusetts Institute of Technology, Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Cambridge, United States
Alfonso Gautieri
Affiliation:
gautieri@MIT.EDU, Politecnico di Milano, Milan, Italy
Sinan Keten
Affiliation:
keten@mit.edu, Massachusetts Institute of Technology, Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Cambridge, United States
Markus J Buehler
Affiliation:
mbuehler@MIT.EDU, Massachusetts Institute of Technology, Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Cambridge, United States
Get access

Abstract

Alport Syndrome is a genetic disease characterized by the breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level mechanisms of this disease utilizing a bottom-up computational materiomics approach focused on the mutation associated with the most severe form of Alport Syndrome. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of a single-residue glycine substitution mutation are studied in a short segment of a collagen type IV tropocollagen molecule. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration with the kink located at the mutation site and a significant alteration of the molecule’s stress-strain response and stiffness.

Type
Research Article
Copyright
Copyright © Materials Research Society 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

[1] Alberts, B. et al., Molecular Biology of the Cell (Taylor & Francis, New York, 2002).Google Scholar
[2] Fratzl, P., and Weinkamer, R., Progress in Materials Science 52, 1263 (2007).10.1016/j.pmatsci.2007.06.001CrossRefGoogle Scholar
[3] Buehler, M. J., and Yung, Y. C., Nature Materials 8, 175 (2009).10.1038/nmat2387CrossRefGoogle Scholar
[4] Vincent, J. F. V., Structural biomaterials (Princeton University Press, Princeton, N.J., 1990).Google Scholar
[5] Ritchie, R. O., Buehler, M. J., and Hansma, P., Physics Today in press (2009).Google Scholar
[6] Prockop, D. J., and Kivirikko, K. I., N Engl J Med 311, 376 (1984).10.1056/NEJM198408093110606CrossRefGoogle Scholar
[7] Prockop, D. J., and Kivirikko, K. I., Annu Rev Biochem 64, 403 (1995).10.1146/annurev.bi.64.070195.002155CrossRefGoogle Scholar
[8] Glorieux, F. H., Journal Of Clinical Investigation 115, 1142 (2005).10.1172/JCI25148CrossRefGoogle Scholar
[9] Rauch, F., and Glorieux, F. H., Lancet 363, 1377 (2004).10.1016/S0140-6736(04)16051-0CrossRefGoogle Scholar
[10] Hudson, B. G. et al., New England Journal of Medicine 348, 2543 (2003).10.1056/NEJMra022296CrossRefGoogle Scholar
[11] Richardson, D., Shires, M., and Davison, A. M., Nephrology Dialysis Transplantation 16, 1291 (2001).10.1093/ndt/16.6.1291CrossRefGoogle Scholar
[12] Burk, S. E., and Jakobiec, F. A., International Ophthalmology Clinics 38, 163 (1998).10.1097/00004397-199803810-00014CrossRefGoogle Scholar
[13] Fujii, H. et al., Clinical and Experimental Nephrology 12, 159 (2008).10.1007/s10157-007-0022-5CrossRefGoogle Scholar
[14] Kuroki, A. et al., Kidney International 73, 364 (2008).10.1038/sj.ki.5002682CrossRefGoogle Scholar
[15] Buehler, M. J., Keten, S., and Ackbarow, T., Progress in Materials Science 53, 1101 (2008).10.1016/j.pmatsci.2008.06.002CrossRefGoogle Scholar
[16] Gautieri, A., Uzel, S. et al., Biophysical Journal (in submission).Google Scholar
[17] Gautieri, A. et al., Protein Science 18, 161 (2009).Google Scholar
[18] Lazaridis, T., and Karplus, M., Proteins-Structure Function And Genetics 35, 133 (1999).10.1002/(SICI)1097-0134(19990501)35:2<133::AID-PROT1>3.0.CO;2-N3.0.CO;2-N>CrossRef3.0.CO;2-N>Google Scholar
[19] Lu, H. et al., Biophysical Journal 75, 662 (1998).10.1016/S0006-3495(98)77556-3CrossRefGoogle Scholar
[20] Buehler, M. J., J. Mater. Res. 21, 1947 (2006).10.1557/jmr.2006.0236CrossRefGoogle Scholar
[21] Gautieri, A., Buehler, M. J., and Redaelli, A., Journal of the Mechanical Behavior of Biomedical Materials 2 130 (2009).10.1016/j.jmbbm.2008.03.001CrossRefGoogle Scholar
[22] Sun, Y. L. et al., Journal Of Biomechanics 37, 1665 (2004).10.1016/j.jbiomech.2004.02.028CrossRefGoogle Scholar
[23] Sasaki, N., and Odajima, S., Journal Of Biomechanics 29, 1131 (1996).10.1016/0021-9290(96)00024-3CrossRefGoogle Scholar

Save article to Kindle

To save this article to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen
Available formats
×

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen
Available formats
×

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Alport Syndrome mutation changes molecular structure and nanomechanics of type IV tropocollagen
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *