Article

Identifying the amylome, proteins capable of forming amyloid-like fibrils

Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095-1570, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2010; 107(8):3487-92. DOI: 10.1073/pnas.0915166107
Source: PubMed

ABSTRACT 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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    • "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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    Biomaterials 06/2015; 54. DOI:10.1016/j.biomaterials.2015.03.002 · 8.31 Impact Factor
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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] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloids are highly ordered protein/peptide aggregates associated with human diseases as well as various native biological functions. Given the diverse range of physiochemical properties of amyloids, we hypothesized that higher order amyloid self-assembly could be used for fabricating novel hydrogels for biomaterial applications. For proof of concept, we designed a series of peptides based on the high aggregation prone C-terminus of Ab42, which is associated with Alzheimer's disease. These Fmoc protected peptides self assemble to b sheet rich nanofibrils, forming hydrogels that are thermoreversible, non-toxic and thixotropic. Mechanistic studies indicate that while hydrophobic, pep interactions and hydrogen bonding drive amyloid network formation to form supramolecular gel structure, the exposed hydro-phobic surface of amyloid fibrils may render thixotropicity to these gels. We have demonstrated the utility of these hydrogels in supporting cell attachment and spreading across a diverse range of cell types. Finally, by tuning the stiffness of these gels through modulation of peptide concentration and salt concentration these hydrogels could be used as scaffolds that can drive differentiation of mesenchymal stem cells. Taken together, our results indicate that small size, ease of custom synthesis, thixotropic nature makes these amyloid-based hydrogels ideally suited for iomaterial/nanotechnology applications.
    Biomaterials 03/2015; · 8.31 Impact Factor
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    • "We characterized the aggregation properties of MBP-1 in detail. We pinpointed several aggregation-prone regions using ZipperDB, an algorithm capable of identifying segments with a high likelihood to form steric zippers, pairs of b sheets that form the spines of amyloid fibers (Sawaya et al., 2007; Goldschmidt et al., 2010). These include residues 9–14, 26–38, 41–54, and 89–97 (Figure 3A). "
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    Molecular Cell 02/2015; DOI:10.1016/j.molcel.2015.01.026 · 14.46 Impact Factor
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