Molecular recognition and structural plasticity in amyloid–nucleic acid complexes

Emerging evidence highlights the importance of the interactions between amyloidogenic proteins and nucleic acids in both pathological and functional amyloid systems. Here, we review the current knowledge on the mechanisms by which nucleic acids modulate amyloid assembly and structure, highlighting conserved paradigms that govern these interactions. Drawing from studies of prion protein, amyloid-β, α-synuclein, and functional bacterial amyloids, we describe how nucleic acids act as cofactors in amyloidogenesis and influence the biological roles of these systems. Despite these studies, key questions remain regarding the structural specificity, sequence dependence, and biophysical principles underlying these interactions. Biophysical and structural tools such as NMR spectroscopy and cryo-EM offer exciting opportunities to resolve these gaps and deepen our understanding of how nucleic acids shape amyloid formation, function, and pathology.