Inhibitors of Amyloid Toxicity Based on -sheet Packing of A
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- 作者：Takeshi Sato ; Pascal Kienlen-Campard ; Mahiuddin Ahmed ; Wei Liu ; Huilin Li ; James I. Elliott ; Saburo Aimoto ; Stefan N. Constantinescu ; Jean-Noel Octave ; and Steven O. Smith
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：May 2, 2006
- 年：2006
- 卷：45
- 期：17
- 页码：5503 - 5516
- 全文大小：778K
- 年卷期：v.45,no.17(May 2, 2006)
- ISSN：1520-4995
文摘
Amyloid fibrils associated with Alzheimer's disease and a wide range of other neurodegenerativediseases have a cross 
-sheet structure, where main chain hydrogen bonding occurs between -strands inthe direction of the fibril axis. The surface of the -sheet has pronounced ridges and grooves when theindividual -strands have a parallel orientation and the amino acids are in-register with one another. Herewe show that in A amyloid fibrils, Met35 packs against Gly33 in the C-terminus of A40 and againstGly37 in the C-terminus of A42. These packing interactions suggest that the protofilament subunits aredisplaced relative to one another in the A40 and A42 fibril structures. We take advantage of thiscorrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternatingglycine and aromatic residues on one face of a -strand. We show that peptide inhibitors based on aGxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature A fibrils asassayed by thioflavin T fluorescence, electron microscopy, and solid-state NMR spectroscopy. Thealternating large and small amino acids in the GxFxGxF sequence are complementary to the correspondingamino acids in the IxGxMxG motif found in the C-terminal sequence of A40 and A42. Importantly,the designed peptide inhibitors significantly reduce the toxicity induced by A42 on cultured rat corticalneurons.
-sheet structure, where main chain hydrogen bonding occurs between -strands inthe direction of the fibril axis. The surface of the -sheet has pronounced ridges and grooves when theindividual -strands have a parallel orientation and the amino acids are in-register with one another. Herewe show that in A amyloid fibrils, Met35 packs against Gly33 in the C-terminus of A40 and againstGly37 in the C-terminus of A42. These packing interactions suggest that the protofilament subunits aredisplaced relative to one another in the A40 and A42 fibril structures. We take advantage of thiscorrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternatingglycine and aromatic residues on one face of a -strand. We show that peptide inhibitors based on aGxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature A fibrils asassayed by thioflavin T fluorescence, electron microscopy, and solid-state NMR spectroscopy. Thealternating large and small amino acids in the GxFxGxF sequence are complementary to the correspondingamino acids in the IxGxMxG motif found in the C-terminal sequence of A40 and A42. Importantly,the designed peptide inhibitors significantly reduce the toxicity induced by A42 on cultured rat corticalneurons.