This superfamily includes the tetratricopeptide repeat (TPR) domain found in a great variety of proteins involved in protein-protein interactions, cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis, the assembly of multiprotein complexes and protein folding. The TPR motif has been identified in various different organisms, ranging from bacteria to humans.

The domain consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. It has a multi-helical fold which consists of two curved layers of alpha helices arranged in a regular right-handed superhelix, where the repeats that make up this structure are arranged about a common axis. These superhelical structures present an extensive solvent-accessible surface that is well suited to binding large substrates such as proteins and nucleic acids. The TPR is likely to be an ancient repeat, since it is found in eukaryotes, bacteria and archaea, whereas the PPR repeat is found predominantly in higher plants. The superhelix formed from these repeats can bind ligands at a number of different regions, and has the ability to acquire multiple functional roles.

The X-ray structure of a domain containing three TPRs from protein phosphatase 5 revealed that TPR adopts a helix-turn-helix arrangement, with adjacent TPR motifs packing in a parallel fashion, resulting in a spiral of repeating anti-parallel alpha-helices. The TPR domain of PP5 presents an additional 'capping and/or solubility' helix at the C terminus. This extra helix is not a unique characteristic of PP5; an equivalent is present in almost all TPR structures solved to date. It could be speculated that this helix is essential for the solubility or stability of these isolated domains.

The two helices are denoted helix A and helix B. The packing angle between helix A and helix B is 24 degrees within a single TPR and generates a right-handed superhelical shape. Helix A interacts with helix B and with helix A' of the next TPR. Two protein surfaces are generated: the inner concave surface is contributed to mainly by residue on helices A, and the other surface presents residues from both helices A and B.

Malfunctioning of a TPR-containing protein has been linked with human diseases, such as Leber congenital amaurosis, chronic granulomatous disease and Down syndrome.

Pfam clan [PfamClan:CL0020], INTERPRO:IPR011990,DOI:10.1016/j.tibs.2003.10.007