Multiple Super-Secondary Structures in Leucine-Rich Repeats with Dual Characteristics

Background: Tandem leucine-rich repeats (LRRs) are typically classified into eleven types; however, several variant motifs have also been reported. Here, we identified new LRR variants that exhibit dual characteristics of two distinct types. We investigated how the dual characteristics influence the structure and function of LRRs. Methods: We conducted sequence similarity searches using the protein database and analyzed sequence features. We also characterized the structural features of these LRR variant motifs using solved structures and AlphaFold models and investigated their potential biological functions through domain analysis. Results: Of the identified 3222 proteins, approximately 60% originate from the bacterial PVC superphylum. The variants were classified into two groups: one defined by the consensus sequence LxxLxLxx(C/T)xzI TDxxLxx(L/F)xx(L/C)xx, and the other by LxxLxLxxCxxI TDxxLxxLxxLP (where “z” denotes a deletion). The LRRs highly similar to the variants are occasionally observed in solved structures and comprise three types of super-secondary structures (SSSs): β-strand–α-helix adjoining a 3(10)-helix–β-strand, β-strand–3(10)-helix–β-strand, and β-strand–3(10)-helix adjoining an α-helix–β-strand. The AlphaFold models adopt these SSSs and, in addition, include the SSS of the β–α–β motif. Functional annotation identified kinase and F-box domains in a subset of these LRR proteins. Conclusions: The coexistence of these four SSSs and the high frequency of the first SSS appear to reflect the dual characteristics of the LRR variants. The LRR variant-containing proteins suggest potential roles in bacterial immunity and ubiquitination. The present findings expand the structural diversity of LRR proteins and provide new insights into their functional roles.