By David Warmflash
What do Alzheimer disease, type 2 diabetes, rheumatoid arthritis, Parkinson disease, malaria, and spider webs all have in common? You may have been thinking of degenerative conditions at first, but seeing malaria on the list, you may have grunted, and maybe again upon seeing my inclusion of spider webs. But the answer is that they all are connected with amyloid. Rather than referring to any specific protein, amyloid is a protein that has been altered in terms of its three-dimensional structure. While the properties of a protein depend on the identities of its amino acid building blocks and the sequence in which they are linked together, the functional groups on the various amino acids cause the amino acid chain to fold and twist in various ways. Due to non-covalent forces, such as hydrogen bonding, sections of the amino acid chains bend and twist into what’s known as the protein’s secondary structure (as opposed to the primary structure, the amino acid sequence itself), consisting of regular patterns, such as sheets and coils. The chain then folds into a tertiary structure, a more complex shape that is unique to the particular protein.
Often, a protein has more than one normal tertiary structure, known as conformations; these switch back and forth as part of normal biochemical function. For instance, the four chains of a hemoglobin molecule normally undergo conformational changes, based on whether they are carrying oxygen molecules and based on the concentration of carbon dioxide, the pH, and various other factors. This adjusts the hemoglobin molecule’s affinity for oxygen dependent on what the hemoglobin is doing at the moment, for instance receiving oxygen in the lungs or releasing it in body tissues.
Rather than corresponding to a change limited to a protein’s tertiary structure, amyloid is a protein that has been altered in a way that reaches the level of secondary structure. This is different from a mutation that changes the primary structure by replacing, adding, or eliminating an amino acid, but the effect can be just as powerful. It’s not always a pathologic effect. Certain amyloid proteins actually are functional and this may include components of the spider web silk (from certain spiders), which is similar to amyloid fibrils in nanostructure.
Additionally, amyloid-like fibrils appear to be normal component of the coating around Plasmodium falciparum, one of the parasites that cause malaria.
So what is amyloid, structurally? One type of secondary structure that often forms in an amino acid chain is a b-sheet. It consists of parallel strands, each several amino acids long, that are linked side to side by hydrogen bonds, forming a regular sheet with pleats like an accordion. It’s normal to have b-sheets within a protein that’s folded into its tertiary structure, and many proteins normally have quaternary structure, consisting of more than one subunit (each formed from its own amino acid chain) linked together. Built of four subunits, hemoglobin is a good example of a molecule with quaternary structure. However, in amyloid, secondary structure is altered such that there is an excessive amount of b-sheets, and these link up with the b-sheets of neighboring molecules, producing an enormous quaternary structure. Called b-amyloid, this material has distinct characteristics on histopathology analysis. It is present as amyloid plaque in brain tissue in settings of Alzheimer disease and certain other conditions, such as cerebral amyloid angiopathy, while other types of amyloid in the diseased tissues associated with Parkinson disease, rheumatoid arthritis, type 2 diabetes, and various other conditions.
With disruption so deep into the molecular structure, developing treatment for amyloid conditions seems overwhelming. However the regularity of the transformed material that makes the plaques may also constitute an Achilles heel. When switching from their normal structure to amyloid, the involved proteins go through a transition state. In a recent study, investigators synthesized secondary structure known as an a-sheet, which is complimentary to b-sheets, so it can be used as a detector.
The strategy, therefore, is to develop a-sheet compounds as detectors for amyloid diseases in their early states, and eventually it is thought that the same approach (i.e., binding the b-sheets of amyloid) will evolve into an a-sheet containing drug treatment. Thus, while various amyloid diseases tend to manifest very differently from one another, over the years to come, they may end up being diagnosed and treated by similar methods.
David Warmflash, M.D., is an astrobiologist, science writer, and physician. He is principal investigator on a Planetary Society-sponsored investigation of the effects of the space environment on organisms.