Protein Tetratricopeptide Repeat and the Companion Non-tetratricopeptide Repeat Helices: Bioinformatic Analysis of Interhelical Interactions

Abstract

The tetratricopeptide repeat (TPR) of proteins consists of a 34-amino acid, alpha-helical motif that comprises a pattern of small and large hydrophobic residues, leading to a recognizable signature sequence. Structural and functional studies have documented that tandem TPRs form a superhelix that interacts with client molecules through strategically placed amino acids. Interestingly, most of the known TPRs are flanked by alpha-helices that lack the TPR signature but often appear as a continuation of the TPR superhelix. The exact role and specificity of these TPR-accompanying non-TPR helices have remained a mystery. Here, starting with TPR proteins of known structure, bioinformatic analyses were conducted on these helices, which revealed that they are diverse in sequence, lacking a clear consensus. However, they display significant atomic contacts with the nearest TPR helix and, to some extent, with the next TPR helix over. The majority of these contacts do not use the signature residues of the TPR helix but rather involve hydrophobic side chains on the facing sides. Thus, compared with the TPR helices, these companion helices are generic in nature, and seem to serve as relatively passive gatekeepers, leaving the terminal TPR helices to encode the signature residues that interact with cognate clients.

Evolution of Protein Structure and Stability in Global Warming

“…Moreover, they can be identified, and their secondary structure predicted with confidence, due to the conservation of signature amino acid residues [ 80 ]. A total of ~23,000 TPR and PPR sequences, representing >48,000 α-helices, were analyzed, and the largest concentration of Trp residues were found near the termini of the helices ( Figure 2 ), confirming and extending early observations with different sets [ 102 , 107 ]. Thus, protection by helix-terminal locations are not unique to constitutive thermophiles, but can also help the mesophiles when temperature rises.…”

“…To test if the helix-terminal location of Trp is unique to thermophilic proteins, I analyzed the helices in a large number of helix-rich domains, namely the tetratricopeptide repeat (TPR) and the pentatricopeptide repeat (PPR) [ 101 , 102 , 103 , 104 ]. TPR and PPR are, respectively, 34- and 35-amino acid bi-helical motifs, found in diverse proteins that overwhelmingly belong to mesophiles [ 105 , 106 , 107 ].…”

“… Near-terminal location of tryptophan (Trp) in all helical repeats. The published collections of the tetratricopeptide and pentatricopeptide repeat sequences [ 102 , 103 ] were visually analyzed for the location of Trp residues, and the numbers were plotted, using Excel. The two classic helices of the tetratricopeptide repeat (TPR) ( Top ) and pentatricopeptide repeat (PPR) ( Bottom ) motif are shown as Helix A and Helix B, and their amino acid position numbers are presented on the horizontal axis.…”

The Uniqueness of Tryptophan in Biology: Properties, Metabolism, Interactions and Localization in Proteins

“…These studies were, therefore, extended to analyses of the free energy operating between side chains involving Trp in several randomly selected proteins. The energy values were collected from the ‘interaction energy matrix web server’, described previously [ 75 , 76 ], manually entered in Excel, and those for Phe and Trp were separated out for comparison, since both are aromatic and hydrophobic. For proof-of-concept analysis, values for a total of 202 Phe and 92 Trp residues were tabulated.…”

An Analytical Review of the Structural Features of Pentatricopeptide Repeats: Strategic Amino Acids, Repeat Arrangements and Superhelical Architecture

“…In recent years, we and others have analyzed and presented various features of their sequence, higher order structure, and the arrangement and spacing of the repeat motifs [2][3][4][5][6][7][8][9][10]. Being the better studied member of this family, TPR has been compared and contrasted with PPR [4,[9][10][11][12]. Notwithstanding these studies, the molecular details of the structure of both repeats, particularly PPR, have remained incomplete.…”