Cross-beta sheet conformation (Cross-β)

The cross-beta sheet conformation is the defining structural hallmark of amyloid fibrils, characterized by beta-strands oriented perpendicular to the long axis of the fibril, forming an extended, highly stable hydrogen-bonded network (Eisenberg & Jucker, 2012). This motif arises when normally soluble proteins misfold and polymerize into insoluble aggregates, a process central to the pathogenesis of over 50 human diseases, including Alzheimer's, Parkinson's, and various systemic amyloidoses (Sipe et al., 2016). Because the cross-beta structure is distinct from the native folds of functional proteins, it serves as a highly specific target for therapeutic and diagnostic interventions. Therapeutic strategies targeting this conformation include monoclonal antibodies like Aducanumab and Lecanemab, which are designed to recognize the aggregated state and facilitate its clearance from the brain (Sevigny et al., 2016). Additionally, small molecule tracers such as Florbetapir utilize the repetitive grooves of the cross-beta sheet to bind and provide a signal for Positron Emission Tomography (PET), allowing for the non-invasive monitoring of amyloid burden in clinical settings (Villemagne et al., 2018). Targeting the cross-beta sheet aims to disrupt the progression of proteotoxicity by preventing fibril elongation or enhancing the removal of existing pathological deposits.

Other names

Amyloid cross-beta structureCross-beta foldAmyloid fibril architectureCross-beta sheet motifAmyloid quaternary structure

Drugs and diagnostic agents target the cross-beta sheet conformation by binding to the repetitive hydrophobic grooves or the hydrogen-bonded backbone of the beta-sheets. This interaction can inhibit the recruitment of monomeric proteins into the fibril (aggregation inhibition), stabilize non-toxic oligomeric species, or label the aggregates for immune-mediated clearance (e.g., via microglia) or diagnostic visualization using PET imaging (Eisenberg & Jucker, 2012; Villemagne et al., 2018).