ArticleAmyloidogenic sequences in native protein structures |
| Susan Tzotzos, Andrew J. Doig * |
Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN, United Kingdom
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| email: Andrew J. Doig (andrew.doig@manchester.ac.uk) |
*Correspondence to Andrew J. Doig, Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom
| amyloid secondary structure aggregation hydrogen-bond solvent accessibility |
Numerous short peptides have been shown to form  -sheet amyloid aggregates in vitro. Proteins that contain such sequences are likely to be problematic for a cell, due to their potential to aggregate into toxic structures. We investigated the structures of 30 proteins containing 45 sequences known to form amyloid, to see how the proteins cope with the presence of these potentially toxic sequences, studying secondary structure, hydrogen-bonding, solvent accessible surface area and hydrophobicity. We identified two mechanisms by which proteins avoid aggregation: Firstly, amyloidogenic sequences are often found within helices, despite their inherent preference to form structure. Helices may offer a selective advantage, since in order to form amyloid the sequence will presumably have to first unfold and then refold into a structure. Secondly, amyloidogenic sequences that are found in structure are usually buried within the protein. Surface exposed amyloidogenic sequences are not tolerated in strands, presumably because they lead to protein aggregation via assembly of the amyloidogenic regions. The use of  -helices, where amyloidogenic sequences are forced into helix, despite their intrinsic preference for structure, is thus a widespread mechanism to avoid protein aggregation. |
Received: 11 September 2009; Revised: 10 November 2009; Accepted: 8 December 2009
10.1002/pro.314
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