Analyses of the folding sites of irregular \u03b2-trefoil fold proteins through sequence-based techniques and G\u014d-model simulations

Risako Kimura,Panyavut Aumpuchin,Shoya Hamaue,Takeshi Kikuchi,Takumi Shimomura

doi:10.1186/s12860-020-00271-4

Abstract

BackgroundThe details of the folding mechanisms have not yet been fully understood for many proteins, and it is believed that the information on the folding mechanism of a protein is encoded in its amino acid sequence. β-trefoil proteins are known to have the same 3D scaffold, namely, a three-fold symmetric scaffold, despite the proteins’ low sequence identity among superfamilies. In this study, we extract an initial folding unit from the amino acid sequences of irregular β-trefoil proteins by constructing an average distance map (ADM) and utilizing inter-residue average distance statistics to determine the relative contact frequencies for residue pairs in terms of F values. We compare our sequence-based prediction results with the packing between hydrophobic residues in native 3D structures and a Gō-model simulation.ResultsThe ADM and F-value analyses predict that the N-terminal and C-terminal regions are compact and that the hydrophobic residues at the central region can be regarded as an interaction center with other residues. These results correspond well to those of the Gō-model simulations. Moreover, our results indicate that the irregular parts in the β-trefoil proteins do not hinder the protein formation. Conserved hydrophobic residues on the β5 strand are always the interaction center of packing between the conserved hydrophobic residues in both regular and irregular β-trefoil proteins.ConclusionsWe revealed that the β5 strand plays an important role in β-trefoil protein structure construction. The sequence-based methods used in this study can extract the protein folding information from only amino acid sequence data, and well corresponded to 3D structure-based Gō-model simulation and available experimental results.

Highlights

The details of the folding mechanisms have not yet been fully understood for many proteins, and it is believed that the information on the folding mechanism of a protein is encoded in its amino acid sequence. βtrefoil proteins are known to have the same 3D scaffold, namely, a three-fold symmetric scaffold, despite the proteins’ low sequence identity among superfamilies
Secondary-structure-based multiple sequence alignment and conserved hydrophobic residues Figure 4 shows the results of using STRuctural Alignments of Proteins (STRAP) to align four irregular beta-trefoil proteins with 2RST as a representation of high symmetric beta-trefoil protein
We identify conserved hydrophobic residues based on this alignment

Summary

Introduction

The details of the folding mechanisms have not yet been fully understood for many proteins, and it is believed that the information on the folding mechanism of a protein is encoded in its amino acid sequence. βtrefoil proteins are known to have the same 3D scaffold, namely, a three-fold symmetric scaffold, despite the proteins’ low sequence identity among superfamilies. We extract an initial folding unit from the amino acid sequences of irregular β-trefoil proteins by constructing an average distance map (ADM) and utilizing interresidue average distance statistics to determine the relative contact frequencies for residue pairs in terms of F values. How a βtrefoil protein folds into such a highly symmetrical structure is an interesting problem and has been studied by various researchers [1,2,3,4]. We clarified how the folding information of such a symmetrical β-trefoil protein is encoded in its amino acid sequence in the previous study [5]. There are some β-trefoil proteins containing irregular structures. In such a protein, the three-fold symmetry is partly disturbed. It is fascinating that whether a β-trefoil protein with an irregular structure folds into its native structure via the same folding pathway as a β-trefoil protein with high three-fold symmetry

Methods

Results

Discussion

Conclusion