Mammalian Amyloid Has Useful Role

Protein Folding

Amyloid, an insoluble and fibrous protein aggregate, is usually thought of as a bad actor. It's associated with disorders like Alzheimer's disease and type 2 diabetes, so preventing its formation is considered highly desirable. Now, however, researchers at Scripps Research Institute find for the first time that amyloid also plays a useful or even essential role in mammals (PLoS Biol. 2006, 4, e6).

In mammalian cell experiments, chemistry professor Jeffery W. Kelly, cell biology professor William E. Balch, and coworkers have found that the protein Pmel17 adopts an amyloid fold in cell organelles called melanosomes and provides a template that approximately doubles the rate of polymerization of melanin, a biopolymer that protects cells against UV and oxidative damage. The amyloid also binds and possibly mitigates the toxicity of reactive compounds in melanosomes. The Scripps work elucidates the mechanism of melanin biosynthesis and could also lead to a better understanding of amyloid pathology and to the discovery of other functional, nonpathologic amyloid.

Amyloid with normal function has been found in bacteria and yeast and in spider silk but never in mammals. Amyloid generally forms insoluble plaques that can be highly toxic to mammalian cells. So the finding that amyloid can be beneficial in higher organisms is a significant step forward in understanding the nature of this alternative form of protein structure, comments Christopher M. Dobson, professor of chemical and structural biology at Cambridge University, in England.

Kelly, Balch, and coworkers propose the name amyloidin for functional amyloid, with the expectation that the number and diversity of structures of this type will continue to grow, they write.

This paper adds a new dimension to the increasing evidence that the amyloid structure is a generic form of protein structure, says Dobson, whose group has demonstrated that many ordinary proteins, not just those present in disease states, are capable of forming amyloid fibrils. The new study should fuel still further the search for more examples of the functional use of the amyloid structure.

Robert Tycko of the National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, Md., a specialist in amyloid structure, says the work is quite interesting and comments that it will undoubtedly stimulate future efforts to find additional functional amyloids, elucidate their mechanisms, and possibly develop new uses for amyloid fibrils based on their biological roles.

There are caveats, however. A researcher in the field who requests anonymity comments that the paper's experimental evidence for amyloid-templated biosynthesis is weak. The rate acceleration provided by the fibrils is only 2.2-fold, and if the mechanism invoked by the authors was operating, I would expect at least an order of magnitude greater acceleration.