The occurrence of highly conserved amyloid-forming sequences in Candida albicansProtein amyloids are characteristic of pathological conditions, including neurodegenerative diseases (4,11,17,38). These protein aggregates can also occur naturally in adhesive bacterial curli (3), melanosomes (14), condensed peptide hormone arrays (24), as regulatory prions in yeast (2, 5), and fungal hydrophobins, which are nonantigenic coats to some fungi (1,33,39). Nevertheless, such natural occurrences are relatively few, considering the negative free energy for amyloid formation (28).We have recently discovered that there are amyloid-forming sequences in the cell surface Als adhesins of Candida albicans. Cells that express these adhesins aggregate readily, and the aggregation has amyloid-like properties, including protein conformational shifting, surface birefringence, and ability to bind the amyloid-active dyes Congo red and amino-naphthalene sulfonic acid (ANS) (29). A five-to seven-residue sequence in Als1p, Als3p, and Als5p has extremely high potential for formation of -aggregates, according to the protein state prediction program TANGO (13,27,31). Such -aggregates include amyloids, which are ordered structures with paracrystalline regions of stacked parallel -strands that are perpendicular to the long axis of micrometer-long fibrils. The strands are stabilized by interaction of identical sequences from many protein molecules (31, 32). Where TANGO analyses have shown that specific sequences have -aggregate potentials greater than 20%, an insoluble -aggregate state is likely to form. These -aggregates nucleate formation of amyloids if the proteins can associate to form fibers (13,27,31). Sequences in the conserved 127-residue T region of Als1p, Als3p, and Als5p have -aggregation potentials of Ͼ90% (27). An oligopeptide with this sequence, as well as 412-and 645-residue fragments of Als5p formed authentic amyloids, as determined by characteristic dye binding and fiber morphology. The amyloid-forming sequences were rich in the -branched amino acids Thr, Val, and Ile. This amino acid composition is unusual among proteins in general, but is common in the Thr-rich mid-piece domains of yeast adhesins.Yeasts display many cell-wall-bound adhesins that mediate colonial and biofilm interactions as well as host-pathogen binding (9,21,41). Such adhesins have a common mosaic structure. In general, the adhesins have N-terminal globular binding domains (often immunoglobulin-like or lectin-like), Thr-rich mid-piece sequences including tandem repeats, and 300-to