A Generalized AI View of Tricopeptide Repeats: What’s in a Name

Tricopeptide repeats refer to 30 or more amino acid (aa) repeats, of which the best studied ones are 34-aa and 35-aa long, named Tetratricopeptide and Pentatricopeptide repeats, respectively, and abbreviated as TPR and PPR. Recently, 37-aa and 38-aa repeats (Heptatricopeptide, HPR; Octatricopeptide, OPR) have been reported, but 36-aa repeats or repeats outside the 34–38 range (such as 33-aa or 39-aa) are apparently missing. This review is an analytical discourse of the structural and functional commonalities as well as differences among all tricopeptide repeats. In structure, the use of Artificial Intelligence (AI)-based prediction and experimental 3D structures revealed that regardless of the number of amino acids, these repeats are all alpha-helical in nature, whereby the tandem helices are joined by relatively flexible linkers or spacers to form a superhelix. In function, many tricopeptide repeats bind specific RNA, thus playing important roles in RNA processing and stability. The specificity is determined by the interaction between specific amino acid residues with the nucleotides in the RNA, while the helices offer a scaffold that holds the interacting residues in position. Detailed analysis of various known TPR and PPR revealed conserved amino acids at specific positions, such that they serve as signature motifs. Moreover, extra helices upstream or downstream of the repeat domains often maintain the continuum of the superhelical vortex. Evidently, the overall helicity and the presence of critical amino acid residues in strategic places are more important for the biological function of the tricopeptide repeats than the exact amino acid length of the repeat.