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Review
. 2007 Aug;8(8):737-42.
doi: 10.1038/sj.embor.7401034.

Prevention of amyloid-like aggregation as a driving force of protein evolution

Elodie Monsellier  1 , Fabrizio Chiti
Affiliations
Review

Prevention of amyloid-like aggregation as a driving force of protein evolution

Elodie Monsellier et al. EMBO Rep. 2007 Aug.

Abstract

Uncontrolled protein aggregation is a constant challenge in all compartments of living organisms. The failure of a peptide or protein to remain soluble often results in pathology. So far, more than 40 human diseases have been associated with the formation of extracellular fibrillar aggregates - known as amyloid fibrils - or structurally related intracellular deposits. It is well known that molecular chaperones and elaborate quality control mechanisms exist in the cell to counteract aggregation. However, an increasing number of reports during the past few years indicate that proteins have also evolved structural and sequence-based strategies to prevent aggregation. This review describes these strategies and the selection pressures that exist on protein sequences to combat their uncontrolled aggregation. We will describe the different types of mechanism evolved by proteins that adopt different conformational states including normally folded proteins, intrinsically disordered polypeptide chains, elastomeric systems and multimodular proteins.

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Figures

Figure 1
Figure 1
Sequence and structural adaptations evolved by proteins to counteract amyloid aggregation. (A) Globular proteins have evolved to fold cooperatively into a compact structure, to minimize clusters of consecutive hydrophobic residues and patterns of alternating polar and non-polar residues, and to have a sufficiently high net charge and conserved glycine and proline residues (particularly in loops). Aggregation-promoting regions are present, but they do not have a dramatically high aggregation propensity and are flanked by gatekeeper residues. (B) Intrinsically disordered proteins have few aggregation-promoting regions, a high fraction of proline residues, a high net charge and a low content of hydrophobic residues. (C) Elastomeric proteins, such as elastin, aggregate in a non-amyloid form. To this end, they have evolved high overall hydrophobicity, but also a high proportion of combined glycine and proline residues. Additional adaptations (not shown) involve the protection of peripheral β-strands in all-β globular proteins, and sequence divergence in adjacent domains of multimodular proteins (see text for details). Individual proteins use more than one adaptation described here.
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Elodie Monsellier
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Fabrizio Chiti
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References

    1. Bastolla U, Demetrius L (2005) Stability constraints and protein evolution: the role of chain length, composition and disulfide bonds. Protein Eng Des Sel 18: 405–415 - PubMed
    1. Bastolla U, Moya A, Viguera E, van Ham RC (2004) Genomic determinants of protein folding thermodynamics in prokaryotic organisms. J Mol Biol 343: 1451–1466 - PubMed
    1. Bouchard M, Zurdo J, Nettleton EJ, Dobson CM, Robinson CV (2000) Formation of insulin amyloid fibrils followed by FTIR simultaneously with CD and electron microscopy. Protein Sci 9: 1960–1967 - PMC - PubMed
    1. Bousset L, Thomson NH, Radford SE, Melki R (2002) The yeast prion Ure2p retains its native α-helical conformation upon assembly into protein fibrils in vitro. EMBO J 21: 2903–2911 - PMC - PubMed
    1. Broome BM, Hecht MH (2000) Nature disfavors sequences of alternating polar and non-polar amino acids: implications for amyloidogenesis. J Mol Biol 296: 961–968 - PubMed