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Molecular structure of amyloid and prion fibrils: insights from solid state NMR
A selection of talks on Biochemistry
The ERK1/2 MAPK cascade
- Prof. Melanie H. Cobb
- University of Texas Southwestern Medical Center at Dallas, USA
Amino acid conjugation: mechanism and enzymology
- Dr. Kathleen Knights
- Flinders University, Australia
Hello, I'm Robert Tycko. And in this talk, I will tell you about recent work from my laboratory in which we're using solid state NMR to characterize the molecular structures of amyloid and prion fibrils.
My research group is part of the laboratory of chemical physics of the National Institute of Diabetes and Digestive and Kidney Diseases. We're located on the main National Institutes of Health campus in Bethesda, Maryland. In this talk, I will describe work that was done by two postdocs in my lab Anant Paravastu and Sorin Luca, as well as work we're doing in collaboration with Reed Wickner's Group, also in NIDDK and a number of former members of my group also contributed to this work, including Oleg Antzutkin, now at Lulea University in Sweden, Who got this whole project started, made the first amyloid fibril samples and did the first solid state NMR measurements in my lab. Aneta Petkova, as you will see, carried out many of the structural measurements that led to a structural model for the amyloid fibrils formed by the beta amyloid peptide associated with Alzheimer's disease. Jerry Chan, John Balbach, Yoshitaka also carried out important solid state NMR measurements and helped to develop new solid state NMR techniques that we've used to characterize amyloid fibril structures and Richard Leapman is an electron microscopist at the NIH and we've been collaborating with him as you will see, electron microscopy measurements are very important in providing information that's complementary to the information we get from solid state NMR.
Solid state NMR simply means the application of nuclear magnetic resonance spectroscopy to samples that are not simple liquids or solutions. Solid state NMR techniques are somewhat different from the NMR techniques that are used to determine the molecular structures of soluble proteins. And one of the reasons for the difference is shown here of the left you see a one dimensional proton NMR protein spectrum of a small protein there are many many many resolved proton NMR lines in this one dimensional spectrum and it's the fact that this one dimensional spectrum so well resolved that's largely responsible for the success of multi dimensional solution NMR techniques that are now widely applied to protein structures. On the right you see a solid state NMR spectrum of a much smaller molecule, a tripeptide Ala-Gly-Gly obtained at our highest magnetic fields and with high speed magic angle spinning, a technique that narrows the NMR lines as much as possible. And still, you only see 3 resolved lines in the spectrum. So the much poorer resolution in the Proton NMR spectrum means that the techniques that are used to determine protein structures in solution really don't apply to things like amyloid fibrils, which are not soluble materials. So the techniques and the approaches that we used to investigate molecular structures in solid state NMR have to be different from those that are commonly used in solution NMR. Fortunately for us solid state NMR techniques are applicable to a number of systems and scientific problems that cannot be addressed by solution NMR or by other structural techniques. And amyloid fibrils are an excellent example of that. In this talk, I will say as little as possible about the solid state NMR techniques themselves. I'll try to focus on the information that we've obtained with those techniques. If you want to learn more about the solid state NMR techniques I might suggest you take a look at the quarterly reviews of biophysics article listed here, which gives an introduction to those techniques.