SSNMR-AMYLOIDS · Amyloid fibril structures explored by solid-state NMR
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2006-12-01 → 2008-11-30
- EU contribution
- €173,264
- Participants
- 1
- Scheme
- EIF
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Results in brief
Final Activity Report Summary - SSNMR-Amyloids (Amyloid fibril structures explored by solid-state NMR.)
Prions and amyloid fibrils are associated with several animal and human diseases. Despite the paramount importance of the structural aspects, no atomic resolution structure of a prion in its fibrillar state had been reported. Solid-state NMR is to date the only technique capable of obtaining the structure of such non-crystalline and non-soluble compounds. We have obtained the structure of amyloid fibrils produced in vitro from the prion-forming domain (residues 218-289) of the HET-s prion from the filamentous fungus Podospora anserina using solid-state NMR techniques. These results give a structural explanation of the stability of the amyloid fibrils. The HET-s(218-289) prion forms a left-handed beta-solenoid, of which each molecule represents two helical windings. This beta-solenoid is stabilized not only by the H-bond network formed by the parallel stacking of the beta-strands, but also by three salt-bridges, two asparagine-ladders, and the presence of a solvent-protected rigid triangular hydrophobic core. Furthermore, an improved protocol for structure determination of amyloid fibrils using solid-state NMR techniques is proposed on this example.
Data: CORDIS, © European Union
Project objective
Amyloid fibrils are self-assembled filamentous structures associated with a wide variety of severely debilitating human pathologies like Alzheimers disease, type II diabetes and the transmissible spongiform encephalopathies. Despite the immense medical importance of amyloid fibrils, no atomic-resolution structures are available for these materials yet. The aim of the project is to determine the structure of the carboxy-terminal part of the prion protein HET-s in its fibrillar state using solid-state NMR.For this fragment, the structure-infectivity correlation has been established, and the host laboratory has already collected information about secondary structure elements. Solid-state NMR is to date the only technique capable of obtaining the structure of such non-crystalline compounds. The state-of-the art methods in solid-state NMR of the host will be combined with the knowledge of the fellow in liquid crystal NMR to provide accurate structural restraints and obtain a structure at atomic resolution. In particular, new NMR experiments will be implemented using fully labelled and axially oriented protein samples. The information obtained by solid-state NMR will be completed with Electron Diffraction and Atomic Force Microscopy data. The results for the HET-s fibrillar system will give a detailed molecular explanation of the characteristic properties of the amyloid fibrils, in particular their unusual stability. This will help designing new drugs against amyloid diseases.
Original text from CORDIS.
Participants
- EIDGENOSSICHE TECHNISCHE HOCHSCHULE, ZURICH · ZURICHCoordinatorCity levelSwitzerland
Links
Data: CORDIS, © European Union