Intrinsic Disorder in Tetratricopeptide Repeat Proteins.

Nathan W Van Bibber,Bin Xue,Roy Khalife,Vladimir N Uversky,Cornelia Haerle

doi:10.3390/ijms21103709

Abstract

Among the realm of repeat containing proteins that commonly serve as “scaffolds” promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination. It is known that many repeat-containing proteins are characterized by high levels of intrinsic disorder, and that many protein tandem repeats can be intrinsically disordered. Furthermore, it seems that TPR-containing proteins share many characteristics with hybrid proteins containing ordered domains and intrinsically disordered protein regions. However, there has not been a systematic analysis of the intrinsic disorder status of TPR proteins. To fill this gap, we analyzed 166 human TPR proteins to determine the degree to which proteins containing TPR motifs are affected by intrinsic disorder. Our analysis revealed that these proteins are characterized by different levels of intrinsic disorder and contain functional disordered regions that are utilized for protein-protein interactions and often serve as targets of various posttranslational modifications.

Highlights

The predominant “lock-and-key” model of protein functionality, according to which the biological function of a protein is determined by its highly ordered structure defined by its unique amino acid sequence [1], has obscured the fact that proteins without unique structure might have biological functions
Peculiarities of the distribution of tetratricopeptide repeats (TPRs) repeats within the amino acid sequences of TPR proteins are illustrated by Figure 2C, which indicates TPR repeats can be found in different parts of proteins, they are less likely to be C-terminal
This article summarizes the results of comprehensive bioinformatics and computational analysis of the intrinsic disorder predisposition of human proteins possessing Tetratricopeptide Repeats (TPRs)

Summary

Introduction

The predominant “lock-and-key” model of protein functionality, according to which the biological function of a protein is determined by its highly ordered structure defined by its unique amino acid sequence [1], has obscured the fact that proteins without unique structure might have biological functions. Complex and highly heterogeneous structural ‘anatomy’ of IDPs/IDPRs contributes to their specific molecular ‘physiology’, where differently (dis)ordered structural elements possess well-defined specific functions [43], thereby allowing a protein molecule to be multifunctional (i.e., involved in interaction with, regulation of, and controlled by multiple structurally unrelated partners) [44]. These same features that are functionally advantageous in tightly regulated disordered proteins can become detrimental, when ID in proteins runs amok. Data on the prevalence of intrinsic disorder in human TPR proteins may suggest yet another possible route for the sophisticated pathogenicity attributed to these proteins

Per-Residue Intrinsic Disorder Predisposition of Human TPR Proteins

35 Supplementary

Structural Properties of Human TPR Proteins

Computational Characterization of Intrinsic Disorder in Human TPR Proteins

Computational Evaluation of Interactability of the Human TPR Proteins

Conclusions