M.R. Sawaya

Plethora of Secretory Amyloids Protein aggregation and the formation of amyloids are associated with several dozen pathological conditions in humans, including Alzheimer's disease, Parkinson's disease, and type II diabetes. In addition, a few functional amyloid systems are known: the prions of fungi, the bacterial protein curli, the protein of chorion of the eggshell of silkworm, and the amyloid protein Pmel-17 involved in mammalian skin pigmentation. Now Maji et al. (p. 328 , published online 18 June) propose that endocrine hormone peptides and proteins are stored in an amyloid-like state in secretory granules. Thus, the amyloid fold may represent a fundamental, ancient, and evolutionarily conserved protein structural motif that is capable of performing a wide variety of functions contributing to normal cell and tissue physiology.

The developing science called structural genomics has focused to date mainly on high-throughput expression of individual proteins, followed by their purification and structure determination. In contrast, the term structural biology is used to denote the determination of structures, often complexes of several macromolecules, that illuminate aspects of biological function. Here we bridge structural genomics to structural biology with a procedure for determining protein complexes of previously unknown function from any organism with a sequenced genome. From computational genomic analysis, we identify functionally linked proteins and verify their interaction in vitro by coexpression/copurification. We illustrate this procedure by the structural determination of a previously unknown complex between a PE and PPE protein from the Mycobacterium tuberculosis genome, members of protein families that constitute approximately 10% of the coding capacity of this genome. The predicted complex was readily expressed, purified, and crystallized, although we had previously failed in expressing individual PE and PPE proteins on their own. The reason for the failure is clear from the structure, which shows that the PE and PPE proteins mate along an extended apolar interface to form a four-alpha-helical bundle, where two of the alpha-helices are contributed by the PE protein and two by the PPE protein. Our entire procedure for the identification, characterization, and structural determination of protein complexes can be scaled to a genome-wide level.