Chemistry matters. Join us to get the news you need.

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Amyloid Fibril Has Unusual Structure

Structural Biology: Researchers generate Alzheimer’s-related fibril, find it has S-shaped configuration

by Celia Henry Arnaud
May 14, 2015 | APPEARED IN VOLUME 93, ISSUE 20

Credit: Nat. Struct. Mol. Biol.
Amyloid β-42’s unusual triple-β-motif is held together by a salt bridge between lysine 28 and alanine 42.
Credit: Nat. Struct. Mol. Biol.
Amyloid β-42’s unusual triple-β-motif is held together by a salt bridge between lysine 28 and alanine 42.

Many scientists believe that plaques made of amyloid peptide contribute to brain degeneration in people with Alzheimer’s disease. Moreover, fibrils of a 42-amino-acid fragment of this peptide are increasingly thought to be the main culprits in triggering plaque formation. But structural information about these fibrils has been hard to come by because they are heterogeneous.

Yoshitaka Ishii of the University of Illinois, Chicago, and coworkers now report generating a homogeneous Aβ-42 fibril in vitro and obtaining a model of its structure with solid-state nuclear magnetic resonance spectroscopy (Nat. Struct. Mol. Biol. 2015, DOI: 10.1038/nsmb.2991). The structure differs significantly from that of Aβ-40, Aβ-42’s shorter and more abundant sibling, which has also been implicated in Alzheimer’s.

Previously reported Aβ-40 fibrils are U-shaped with parallel β-sheets connected by a flexible loop. In contrast, this particular Aβ-42 fibril contains three connected β-sheets that adopt an S-shaped configuration.

Different interactions stabilize the Aβ-40 and Aβ-42 structures. The shorter peptide is held together by a salt bridge between lysine 28 and aspartic acid 23. Instead of that interaction, Aβ-42 forms a salt bridge between lysine 28 and alanine 42, a residue that doesn’t exist on the shorter peptide.

Previous structural studies by Robert Tycko at the National Institutes of Health and others have shown that amyloid-β fibrils having a given sequence can adopt multiple structures with subtle differences in configuration.

The new work is important, Tycko says, “because it demonstrates that conformational variations in amyloid-β fibrils can be dramatic.” In addition, the study suggests an explanation for why fibrils formed by Aβ-40 and Aβ-42 don’t “cross-seed,” or trigger one another to form fibrils, he says. “It remains to be seen whether the fibril structure described in this paper exists in human brain tissue,” he notes.

If the structure is found in the brain, drugs that have already been designed to optimally obstruct an arched β-motif in Aβ-40 may not work as well against Alzhei­mer’s, which might be caused by the more toxic Aβ-42 fibrils, Ishii and coworkers say.



This article has been sent to the following recipient:

Nathan (May 15, 2015 9:31 AM)
I always thought that a salt bridge is formed between oppositely charged residues. How come a salt bridge is formed here between lysine and alanine?
Wilbur (May 15, 2015 10:53 AM)
Because Ala42 is C-terminal of Aβ-42; also see figure
Anonymous (May 15, 2015 4:44 PM)
I guess it's terminal Ala
Martin (May 16, 2015 7:33 AM)
It's the C-terminal carboxylate
Celia Arnaud (May 18, 2015 7:20 AM)
The three other responders are right. Ala-42 is the C-terminus of AB-42.
Nathan (May 19, 2015 9:40 AM)
Hi All

thanks so much for the response. So, any amino acid especially hydrophobic ones,can have this interaction with Lysine 28 , it doesn't have to be Alanine right?

Celia Arnaud (May 26, 2015 6:19 AM)
It seems to me that the real point is that AB-42 is long enough to have this extra interaction that stabilizes the third beta sheet. If that is true, it could probably be any amino acid, but alanine is what happens to be in AB-42.

Leave A Comment

*Required to comment