Hostname: page-component-848d4c4894-x5gtn Total loading time: 0 Render date: 2024-04-30T17:53:19.933Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  31 January 2011

Maya Srinivasan ,
Sebastien G.M. Uzel ,
Alfonso Gautieri ,
Sinan Keten  and
Markus J Buehler
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.

Keywords

biologicalelastic propertiesdefects
Type
Research Article
Information
MRS Online Proceedings Library (OPL) , Volume 1187: Symposium KK – Structure-Property Relationships in Biomineralized and Biomimetic Composites , 2009 , 1187-KK01-09
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.2007.06.001Google Scholar
[3] Buehler, M. J., and Yung, Y. C., Nature Materials 8, 175 (2009).10.1038/nmat2387Google 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/NEJM198408093110606Google Scholar
[7] Prockop, D. J., and Kivirikko, K. I., Annu Rev Biochem 64, 403 (1995).10.1146/annurev.bi.64.070195.002155Google Scholar
[8] Glorieux, F. H., Journal Of Clinical Investigation 115, 1142 (2005).10.1172/JCI25148Google Scholar
[9] Rauch, F., and Glorieux, F. H., Lancet 363, 1377 (2004).10.1016/S0140-6736(04)16051-0Google Scholar
[10] Hudson, B. G. et al., New England Journal of Medicine 348, 2543 (2003).10.1056/NEJMra022296Google Scholar
[11] Richardson, D., Shires, M., and Davison, A. M., Nephrology Dialysis Transplantation 16, 1291 (2001).10.1093/ndt/16.6.1291Google Scholar
[12] Burk, S. E., and Jakobiec, F. A., International Ophthalmology Clinics 38, 163 (1998).10.1097/00004397-199803810-00014Google Scholar
[13] Fujii, H. et al., Clinical and Experimental Nephrology 12, 159 (2008).10.1007/s10157-007-0022-5Google Scholar
[14] Kuroki, A. et al., Kidney International 73, 364 (2008).10.1038/sj.ki.5002682Google Scholar
[15] Buehler, M. J., Keten, S., and Ackbarow, T., Progress in Materials Science 53, 1101 (2008).10.1016/j.pmatsci.2008.06.002Google 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>Google Scholar
[19] Lu, H. et al., Biophysical Journal 75, 662 (1998).10.1016/S0006-3495(98)77556-3Google Scholar
[20] Buehler, M. J., J. Mater. Res. 21, 1947 (2006).10.1557/jmr.2006.0236Google 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.2008.03.001Google Scholar
[22] Sun, Y. L. et al., Journal Of Biomechanics 37, 1665 (2004).10.1016/j.jbiomech.2004.02.028Google Scholar
[23] Sasaki, N., and Odajima, S., Journal Of Biomechanics 29, 1131 (1996).10.1016/0021-9290(96)00024-3Google Scholar