文档介绍：Amyloidogenic sequences in native
protein structures
Susan Tzotzos and Andrew J. Doig*
Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN, United Kingdom
Received 11 September 2009; Revised 10 November 2009; Accepted 8 December 2009
DOI:
Published online 21 December 2009
Abstract: Numerous short peptides have been shown to form b-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 b 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 b structure.
Secondly, amyloidogenic sequences that are found in b 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
a-helices, where amyloidogenic sequences are forced into helix, despite their intrinsic preference
for b structure, is thus a widespread mechanism to avoid protein aggregation.
Keywords: amyloid; secondary structure; aggregation; hydrogen-bond; solvent accessibility
Introduction amongst which are Alzheimer’s, Huntingdon’s, and
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