Exclusion of the native alpha-helix from the amyloid fibrils of a mixed alpha/beta protein.

Gareth J Morgan, Silva Giannini, Andrea M Hounslow, C Jeremy Craven, Eva Zerovnik, Vito Turk, Jonathan P Waltho, Rosemary A Staniforth

    Research output: Contribution to journalArticlepeer-review


    Members of the cystatin superfamily are involved in an inherited form of cerebral amyloid angiopathy and readily form amyloid fibrils in vitro. We have determined the structured core of human stefin B (cystatin B) amyloid fibrils using quenched hydrogen exchange and NMR. The core contains residues from four of the five strands of the native beta-sheet, delimited by unprotected loop regions analogous to those of the native monomeric structure. However, non-native features are also apparent, the most striking of which is the exclusion of the native alpha-helix. Before forming amyloid in vitro, cystatins dimerise via 3D domain swapping, and assemble into tetramers with trans to cis isomerism of a conserved proline. In the fibril, the hinge loop that forms an extended beta-structure in the dimer remains protected, consistent with the domain-swapping interface being maintained. However, the fibril data are not compatible with a simple 3D domain-swapping model for amyloid formation, and the displacement of the helix points to alternative packing arrangements of native-like beta-structure, in which proline isomerism is important in preventing steric clashing.
    Original languageEnglish
    Pages (from-to)487-498
    Number of pages11
    JournalJournal of molecular biology
    Issue number2
    Publication statusPublished - 11 Jan 2008


    • amyloid
    • cystatin
    • fibril structure
    • hydrogen-deuterium exchange
    • neurodegeneration


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