crossbeta

Crossbeta, sometimes written cross-beta, is a structural motif observed in amyloid fibrils in which beta-strands run perpendicular to the fibril axis and align into extensively packed beta-sheets that form the fibril core. This arrangement contrasts with other protein folds that maintain parallel domains; the cross-beta architecture is a defining feature of amyloids across diverse sequences.

The arrangement produces a characteristic cross-beta diffraction pattern: meridional reflections near 4.7 Å along the fiber axis, and equatorial reflections near 10 Å between beta-sheets, reflecting the spacing of polypeptide strands and sheets. These features are observed in X-ray fiber diffraction studies of amyloid fibers and are also supported by solid-state NMR and cryo-electron microscopy data.

Crossbeta structures occur in many amyloidogenic proteins linked to disease, such as certain variants of amyloid-β, α-synuclein, and prions, but they also appear in functional amyloids used by microorganisms and other organisms for traits like biofilm formation, pigment deposition, or structural scaffolding. The cross-beta motif contributes to the stability and robustness of the fibrils, enabling long-range order despite sequence variability.

Formation is driven by aggregation of polypeptide chains into extended beta-strand conformations, followed by nucleation-dependent polymerization and lateral association. Environmental factors such as pH, ionic strength, concentration, and mutations can influence the propensity to adopt crossbeta architectures.

Understanding crossbeta is central to research on protein misfolding diseases and the design of inhibitors or diagnostic tools, as well as to studies of functional amyloids. Ongoing work uses diffraction, solid-state NMR, cryo-EM, and computational modeling to resolve variations in crossbeta structures among different proteins.