Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci USA

Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095-1570, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2010; 107(8):3487-92. DOI: 10.1073/pnas.0915166107
Source: PubMed


The amylome is the universe of proteins that are capable of forming amyloid-like fibrils. Here we investigate the factors that enable a protein to belong to the amylome. A major factor is the presence in the protein of a segment that can form a tightly complementary interface with an identical segment, which permits the formation of a steric zipper-two self-complementary beta sheets that form the spine of an amyloid fibril. Another factor is sufficient conformational freedom of the self-complementary segment to interact with other molecules. Using RNase A as a model system, we validate our fibrillogenic predictions by the 3D profile method based on the crystal structure of NNQQNY and demonstrate that a specific residue order is required for fiber formation. Our genome-wide analysis revealed that self-complementary segments are found in almost all proteins, yet not all proteins form amyloids. The implication is that chaperoning effects have evolved to constrain self-complementary segments from interaction with each other.

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    • "Lysine residues in PAP248-286, PAP85-120, SEM1, and SEM2 peptides are frequently found within or immediately adjacent to hexapeptides predicted to form self-complementary β-strands (Figure 1C–E, underlined residues), termed steric zippers, which often comprise the spine of amyloid fibrils (Nelson et al., 2005; Goldschmidt et al., 2010; Sievers et al., 2011; Castellano and Shorter, 2012; Frohm et al., 2015). Moreover, the wealth of basic residues in PAP248-286, PAP85-120, and SEM1(45-107) (Figure 1C–E) led us to hypothesize that the lysine-and arginine-specific tweezer, CLR01, but not its derivative CLR03, which lacks hydrophobic sidewalls (Sinha et al., 2011) (Figure 1A,B), might bind to these residues and interfere with fibril assembly. "
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    • "pH, local protein/peptide concentration, salt concentration, temperature, chaperones , reaction surface, solvent, incubation time) form amyloid. In fact, amyloid formation seems to be an intrinsic propensity of polypeptides in general and the beta-sheet based fold an evolutionary highly conserved structure (Dobson, 2004; Chiti and Dobson, 2006; Goldschmidt et al., 2010). "
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    • "Crystal structure of amyloid microcrystal derived from Ab(37e42) showing b-sheet zipper formations (in blue). The structure is shown according to ZipperDB [62] "
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