Background: Vicilin seed storage proteins are translated with N-terminal leader sequences (LSs) that are cleaved to yield the mature protein. These LSs were thought to be unstructured and rapidly degraded. However, Ara h 1 and Jug r 2 LS (A1LS, J2LS) have been identified in seeds, and immunodominant IgE epitopes detected. Here, common sequences containing structured CxxxC-repeat motifs were identified as potential mediators of IgE cross-reactivity despite very low (17%) sequence identity. Method: Linear IgE epitopes were identified by peptide microarrays, in which overlapping 15-mer peptides on glass slides, were incubated with sera from peanut, walnut or dual allergic individuals. Similar epitopes were computationally predicted. Peanut A1LS and walnut J2LS fragments (J2.1, J2.2, J2.3) each with a CxxxC vicilin LS motif were identified, cloned, expressed, purified and their structures solved using solution-NMR to locate and assess epitopes on the structure. Results: A1LS and J2LSs reveal similar helix-turn-helix motifs connected by disulfide bonds between adjacent CxxxC repeats forming α-hairpin structures. Peanut-allergic IgE bound more frequently to the J2LSs, regardless of walnut allergic status or A1LS binding. IgE binding pattern to peptides from both J2LS and A1LS, along with structure and computational predictions, suggest that the structure and conserved amino acid properties of peptides determine cross-reactivity. The properties of LS IgE epitopes were closely related to epitopes in 2S albumins. Conclusion: The shared α-hairpin structure is a stable scaffold that contributes to cross-reactivity despite low sequence identity. Biophysical properties are a better predictor of distant cross-reactivity than traditional measures of evolutionary conservation.