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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    • "Reflecting the intended function of this inhibitor as a rescuer of the activity of p53, we call it ReACp53. RESULTS p53 Amyloid Spine Structure and Its Use to Design a Sequence-Specific Aggregation Inhibitor Several segments in the DNA binding domain of p53 are prone to form an amyloid adhesive segment, termed a steric zipper, as calculated by the ZipperDB algorithm, which identified residues 252–258 as the most aggregation prone in this region (Figure 1A, Goldschmidt et al., 2010). Segment 251–257 has been reported as necessary and sufficient to drive p53 aggregation in cell lines (Ghosh et al., 2014; Xu et al., 2011). "
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    ABSTRACT: Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.
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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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    ABSTRACT: Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
    Full-text · Article · Aug 2015 · eLife Sciences
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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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    Preview · Article · Jul 2015 · Journal of Theoretical Biology
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