It’s easy to see why cryoEM got the latest chemistry Nobel. It is telling us so much. Particularly fascinating to me as a retired neurologist is the structure of the Abeta42 fibril reported in last Friday’s Science (vol. 358 pp. 116 – 119 ’17).
Caveats first. The materials were prepared using an aqueous solution at low pH containing an organic cosolvent — so how physiologic could the structure actually be? It probably is physiologic as the neurotoxicity of the fibrils to neurons in culture was the same as fibrils grown at neutral pH. This still isn’t the same as fibrils grown in the messy concentrated chemical soup known as the cytoplasm. Tending to confirm their findings is the fact that NMR and Xray diffraction on the crystals produced the same result.
The fibrils were unbranched and microns long (implying at least 2,000 layers of the beta sheets to be described). The beta sheets stack in parallel and in register giving the classic crossBeta sheet structure. They were made of two protofilaments winding around each other. Each protofilament contains all 42 amino acids of Abeta42 and all of them form a completely flat beta sheet structure.
Feast your eyes on figure 2 p. 117. In addition to showing the two beta sheets of the two protofilaments, it shows how they bind to each other. Aspartic acid #1 of one sheet binds to lysine #28 of the other. Otherwise the interface is quite hydrophobic. Alanine2 of one sheet binds to alanine42 of the other, valine39 of one sheet binds to valine 39 of the other. Most importantly isoLeucine 41 of one sheet binds to glycine38 of the other.
This is important since the difference between the less toxic Abeta40 and the toxic Abeta 42 are two hydrophobic amino acids Isoleucine 41 and Alanine 42. This makes for a tighter, longer, more hydrophobic interface between the protofilaments stabilizing them.
That’s just a guess. I can’t wait for work on Abeta40 to be reported at this resolution.
A few other points. The beta sheet of each protomer is quite planar, but the planes of the two protomers are tilted by 10 degrees accounting for the helicity of the fibril. The fibril is a rhombus whose longest edge is about 70 Angstroms.
Even better the structure explains a mutation which is protective against Alzheimer’s. This remains the strongest evidence (to me at least) that Abeta peptides are significantly involved in Alzheimer’s disease, therapeutic failures based on this idea notwithstanding. The mutation is a change of alanine2 to threonine which can’t possibly snuggle up hydrophobically to isoleucine nearly as well as alanine did. This should significantly weaken the link between the two protofilaments and make fibril formation more difficult.
The Abeta structure of the paper also explains another mutation. This one increases the risk of Alzheimer’s disease (like many others which have been discovered). It involves the same amino acid (alanine2) but this time it is changed to the more hydrophobic valine, probably resulting in a stronger hydrophobic interaction with isoLeucine41 (assuming that valine’s greater bulk doesn’t get in the way sterically).
Wonderful stuff to think and speculate about, now that we actually have some solid data to chew on.
Chemiotics II 