Publication: Phenotypic effects of EhlersâDanlos syndrome-associated mutation on the FnIII domain of tenascin-X
All || By Area || By Year| Title | Phenotypic effects of EhlersâDanlos syndrome-associated mutation on the FnIII domain of tenascin-X | Authors/Editors* | Shulin Zhuang, Apichart Linhananta, and Hongbin Li |
|---|---|
| Where published* | PROTEIN SCIENCE |
| How published* | Journal |
| Year* | 2010 |
| Volume | 19 |
| Number | 11 |
| Pages | 2231-2239 |
| Publisher | Wiley-Blackwell. |
| Keywords | tenascin-X; EhlersâDanlos syndrome; mutation; single-molecule force spectroscopy; molecular dynamics simulations; mechanotransduction |
| Link | http://onlinelibrary.wiley.com/doi/10.1002/pro.503/abstract |
| Abstract |
Tenascin-X (TNX) is an extracellular matrix (ECM) protein and interacts with a wide variety of molecules in the ECM as well as on the membrane. Deficiency of TNX causes a recessive form of EhlersâDanlos syndrome (EDS) characterized by hyperelastic and fragile skin, easy bruising, and hypermobile joints. Three point mutations in TNX gene were found to be associated with hypermobility type EDS and one of such mutations is the V1195M mutation at the 7th fibronectin Type III domain (TNXfn7). To help elucidate the underlying molecular mechanism connecting this mutation to EDS, here we combined homology modeling, chemical denaturation, single molecule atomic force microscopy, and molecular dynamics (MD) simulation techniques to investigate the phenotypic effects of V1195M on TNXfn7. We found that the V1195M mutation does not alter the three-dimensional structure of TNXfn7 and had only mild destabilization effects on the thermodynamic and mechanical stability of TNXfn7. However, MD simulations revealed that the mutation V1195M significantly alters the flexibility of the C0E loop of TNXfn7. As loops play important roles in proteinâprotein and proteinâligand interactions, we hypothesize that the decreased loop flexibility by V1195M mutation may affect the binding of TNX to ECM molecules and thus adversely affect collagen deposition and fibrillogenesis. Our results may provide new insights in understanding the molecular basis for the pathogenesis of V1195M-resulted EDS. |
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