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- W2564716435 abstract "Candidates for the toxic molecular species in the expanded polyglutamine (polyQ) repeat diseases range from various types of aggregates to “misfolded” monomers. One way to vet these candidates is to develop mutants that restrict conformational landscapes. Previously, we inserted two self-complementary β-hairpin enhancing motifs into a short polyQ sequence to generate a mutant, here called “βHP,” that exhibits greatly improved amyloid nucleation without measurably enhancing β-structure in the monomer ensemble. We extend these studies here by introducing single-backbone H-bond impairing modifications αN-methyl Gln or l-Pro at key positions within βHP. Modifications predicted to allow formation of a fully H-bonded β-hairpin at the fibril edge while interfering with H-bonding to the next incoming monomer exhibit poor amyloid formation and act as potent inhibitors in trans of simple polyQ peptide aggregation. In contrast, a modification that disrupts intra-β-hairpin H-bonding within βHP, while also aggregating poorly, is ineffective at inhibiting amyloid formation in trans. The inhibitors constitute a dynamic version of the edge-protection negative design strategy used in protein evolution to limit unwanted protein aggregation. Our data support a model in which polyQ peptides containing strong β-hairpin encouraging motifs only rarely form β-hairpin conformations in the monomer ensemble, but nonetheless take on such conformations at key steps during amyloid formation. The results provide insights into polyQ solution structure and fibril formation while also suggesting an approach to the design of inhibitors of polyQ amyloid growth that focuses on conformational requirements for fibril and nucleus elongation." @default.
- W2564716435 created "2017-01-06" @default.
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- W2564716435 date "2017-01-01" @default.
- W2564716435 modified "2023-10-14" @default.
- W2564716435 title "Backbone Engineering within a Latent β-Hairpin Structure to Design Inhibitors of Polyglutamine Amyloid Formation" @default.
- W2564716435 cites W1481393922 @default.
- W2564716435 cites W1589545251 @default.
- W2564716435 cites W1901715948 @default.
- W2564716435 cites W1966910457 @default.
- W2564716435 cites W1967491216 @default.
- W2564716435 cites W1967838681 @default.
- W2564716435 cites W1969792259 @default.
- W2564716435 cites W1975403706 @default.
- W2564716435 cites W1976073965 @default.
- W2564716435 cites W1976681078 @default.
- W2564716435 cites W1976817344 @default.
- W2564716435 cites W1978672495 @default.
- W2564716435 cites W1978773812 @default.
- W2564716435 cites W1979706337 @default.
- W2564716435 cites W1981334795 @default.
- W2564716435 cites W1981396716 @default.
- W2564716435 cites W1985474993 @default.
- W2564716435 cites W1988038897 @default.
- W2564716435 cites W1988895895 @default.
- W2564716435 cites W1995460668 @default.
- W2564716435 cites W1996340455 @default.
- W2564716435 cites W1996757196 @default.
- W2564716435 cites W1996937282 @default.
- W2564716435 cites W2000904062 @default.
- W2564716435 cites W2001997725 @default.
- W2564716435 cites W2002869713 @default.
- W2564716435 cites W2004480624 @default.
- W2564716435 cites W2006298998 @default.
- W2564716435 cites W2007524374 @default.
- W2564716435 cites W2010614834 @default.
- W2564716435 cites W2013752458 @default.
- W2564716435 cites W2023338599 @default.
- W2564716435 cites W2030547977 @default.
- W2564716435 cites W2032280304 @default.
- W2564716435 cites W2033439448 @default.
- W2564716435 cites W2038182929 @default.
- W2564716435 cites W2041669759 @default.
- W2564716435 cites W2042521416 @default.
- W2564716435 cites W2042716629 @default.
- W2564716435 cites W2042800995 @default.
- W2564716435 cites W2042904623 @default.
- W2564716435 cites W2048043626 @default.
- W2564716435 cites W2055197343 @default.
- W2564716435 cites W2057673048 @default.
- W2564716435 cites W2058470791 @default.
- W2564716435 cites W2058543711 @default.
- W2564716435 cites W2060617469 @default.
- W2564716435 cites W2065359898 @default.
- W2564716435 cites W2069452881 @default.
- W2564716435 cites W2071327389 @default.
- W2564716435 cites W2072201545 @default.
- W2564716435 cites W2073295365 @default.
- W2564716435 cites W2073394015 @default.
- W2564716435 cites W2073922528 @default.
- W2564716435 cites W2075793654 @default.
- W2564716435 cites W2079250951 @default.
- W2564716435 cites W2082210254 @default.
- W2564716435 cites W2084317099 @default.
- W2564716435 cites W2085467932 @default.
- W2564716435 cites W2089484728 @default.
- W2564716435 cites W2090570211 @default.
- W2564716435 cites W2090786642 @default.
- W2564716435 cites W2092938083 @default.
- W2564716435 cites W2099114485 @default.
- W2564716435 cites W2105747184 @default.
- W2564716435 cites W2121053757 @default.
- W2564716435 cites W2123544060 @default.
- W2564716435 cites W2132629607 @default.
- W2564716435 cites W2137220407 @default.
- W2564716435 cites W2145487893 @default.
- W2564716435 cites W2155767442 @default.
- W2564716435 cites W2169821755 @default.
- W2564716435 cites W2253321251 @default.
- W2564716435 cites W2289015787 @default.
- W2564716435 cites W2293211587 @default.
- W2564716435 cites W2310133706 @default.
- W2564716435 cites W2322974219 @default.
- W2564716435 cites W2331980872 @default.
- W2564716435 cites W2338758241 @default.
- W2564716435 cites W2409941786 @default.
- W2564716435 cites W2410137933 @default.
- W2564716435 cites W2412450093 @default.
- W2564716435 cites W2422996593 @default.
- W2564716435 cites W4211110682 @default.