Title: A comparative study of the relationship between protein structure and beta-aggregation in globular and intrinsically disordered proteins
Authors: Linding, R ×
Schymkowitz, Joost
Rousseau, Frederic
Diella, F
Serrano, L #
Issue Date: Sep-2004
Publisher: Academic Press
Series Title: Journal of Molecular Biology vol:342 issue:1 pages:345-353
Abstract: A growing number of proteins are being identified that are biologically active though intrinsically disordered, in sharp contrast with the classic notion that proteins require a well-defined globular structure in order to be functional. At the same time recent work showed that aggregation and amyloidosis are initiated in amino acid sequences that have specific physico-chemical properties in terms of secondary structure propensities, hydrophobicity and charge. In intrinsically disordered proteins (IDPs) such sequences would be almost exclusively solvent-exposed and therefore cause serious solubility problems. Further, some IDPs such as the human prion protein, synuclein and Tau protein are related to major protein conformational diseases. However, this scenario contrasts with the large number of unstructured proteins identified, especially in higher eukaryotes, and the fact that the solubility of these proteins is often particularly good. We have used the algorithm TANGO to compare the aggregation tendency of a set of globular proteins derived from SCOP and a set of 296 experimentally verified, non-redundant IDPs but also with a set of IDPs predicted by the algorithms DisEMBL and GlobPlot. Our analysis shows that the beta-aggregation propensity of all-alpha, all-beta and mixed alpha/ beta globular proteins as well as membrane-associated proteins is fairly similar. This illustrates firstly that globular structures possess an appreciable amount of structural frustration and secondly that beta-aggregation is not determined by hydrophobicity and beta-sheet propensity alone. We also show that globular proteins contain almost three times as much aggregation nucleating regions as IDPs and that the formation of highly structured globular proteins comes at the cost of a higher beta-aggregation propensity because both structure and aggregation obey very similar physico-chemical constraints. Finally, we discuss the fact that although IDPs have a much lower aggregation propensity than globular proteins, this does not necessarily mean that they have a lower potential for amyloidosis. (C) 2004 Elsevier Ltd. All rights reserved.
ISSN: 0022-2836
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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