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. 2009 Feb 10;6(1):015005.
doi: 10.1088/1478-3975/6/1/015005.

A role for helical intermediates in amyloid formation by natively unfolded polypeptides?

Andisheh Abedini  1 , Daniel P Raleigh
Affiliations

A role for helical intermediates in amyloid formation by natively unfolded polypeptides?

Andisheh Abedini et al. Phys Biol. .

Abstract

Amyloid formation and aberrant protein aggregation have been implicated in more than 15 different human diseases and an even wider range of proteins form amyloid in vitro. From a structural perspective the proteins which form amyloid can be divided into two classes: those which adopt a compact globular fold and must presumably at least partially unfold to form amyloid and those which are unstructured in their monomeric state. Important examples of the latter include the Abeta peptide of Alzheimer's disease, atrial natriuretic factor, calcitonin, pro-calcitonin, islet amyloid polypeptide (IAPP, amylin), alpha-synuclein and the medin polypeptide. The kinetics of amyloid assembly are complex and typically involve a lag phase during which little or no fibril material is formed, followed by a rapid growth stage leading to the beta-sheet-rich amyloid structure. Increasing evidence suggests that some natively unfolded polypeptides populate a helical intermediate during the lag phase. We propose a model in which early oligomerization is linked to helix formation and is promoted by helix-helix association. Recent work has highlighted the potential importance of polypeptide membrane interactions in amyloid formation and helical intermediates appear to play an important role here as well. Characterization of helical intermediates is experimentally challenging but new spectroscopic techniques are emerging which hold considerable promise and even have the potential to provide residue specific information.

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Figures

Figure-1
Figure-1
A highly schematic diagram of one how α-helical intermediates might promote β-structure. α-helices are depicted as cylinders, β-sheet as zig zagging lines and coil regions as curved segments. Initial polypeptide association is driven by the thermodynamic linkage between helix formation and self association (step-1). This generates a high local concentration of a segment of the polypeptide chain which has a high amyloidogenic propensity which leads to initiation of β-structure. The β-structure propagates leading to β-sheet rich assemblies. We stress that the diagram is schematic and is not meant to imply a specific pathway for assembly for any particular system. In particular a range of oligomeric species could be formed. A trimer is depicted here. The diagram invokes a sequential zipping together of the β-strands and unzipping of the helices but this is simply meant to be illustrative and a diversity of pathways is likely. It is also possible that helical intermediates could represents off pathway species and not the on pathway intermediates depicted here.
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