For some years now scientists have been trying to elucidate the physics behind amyloid fibrils, the multimeric and insoluble strands that cause a variety of amyloidoses, including the plaques of Alzheimer’s disease (see related news item). Today in Nature Structural Biology, researchers in Todd Yeates’ lab at the University of California, Los Angeles, report that the fibrils may be formed by a sucessive head-to-head and tail-to-tail arrangement of individual subunits.
This lab had previously shown that in fibrils of transthyretin, a protein studied as a model for amyloid formation, monomers can bind each other through their respective F β-strands, one of eight present in the molecule (the β-strands are labeled with consecutive letters of the alphabet). But this head-to-head arrangement would limit to just two the number of monomers that can be strung together. Clearly, some other forces must be at work to facilitate fibril growth.
First author Ahmed Serag et al. used site-directed spin labeling, which measures the distance between amino acids, to probe fibrils of transthyretin for likely spots where the monomers may be binding to each other. They found that amino acids on the B β-strands of individual subunits draw near as fibrils form—the gap between two cysteine31s, for example, shortens to 8 Angstroms—indicating that two subunits can bind via their B strands. As the B and F strands are at opposite ends of the molecule it suggests that fibrils form when subunits alternately stack head-to-head and tail-to-tail.
But why does transthyretin only form amyloid fibrils in certain individuals? The authors suggest that for a stable fibril to form, the B β-strands, normally protected from each other by the C and D β-strands, must be exposed. This could happen if the C or D strands are mutated or exposed to an acidic environment, scenarios that have been shown to be fulfilled in vivo.
Serag et al’s model for fibril formation is consistent with work from Jane and David Richardson’s lab at Duke University, Durham, North Carolina, which suggests several mechanisms that have evolved over time to protect proteins with extensive β-strand structure from aggregating to each other. In many cases a single charged amino acid in the middle of an exposed β-strand would suffice.—Tom Fagan
- Richardson JS, Richardson DC. Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2754-9. PubMed.
- Serag AA, Altenbach C, Gingery M, Hubbell WL, Yeates TO. Arrangement of subunits and ordering of beta-strands in an amyloid sheet. Nat Struct Biol. 2002 Oct;9(10):734-9. PubMed.