Evolu-sec Package

The Evolu-sec package forms part of the research project reported in Evolutionary model of protein secondary structure capable of revealing new biological relationships. View the published article

The package contains phylogenetic analysis tools based on an evolutionary model of protein secondary structure. The analysis focuses on phylogenetic tree inference (left), evolutionary distance estimation (top), and ancestral secondary structure reconstruction (bottom and right). The centre of the figure presents the model described in Table 1.

The project abstract appears in the next section. The data and software used for model development are available under Supplementary Data.

Evolutionary model of protein secondary structure capable of revealing new biological relationships
Jhih-Siang Lai, Burkhard Rost, Bostjan Kobe, and Mikael Bodén
School of Chemistry and Molecular Biosciences, The University of Queensland
Contact: Jhih-Siang Lai

Abstract

Ancestral sequence reconstruction has had recent success in decoding the origins and the determinants of complex protein functions. However, attempts to reconstruct ancient proteins and phylogenetic analyses of remote homologues must handle extreme amino-acid sequence diversity resulting from extended periods of evolutionary change [2]. We exploited the wealth of protein structures in the Protein Data Bank (PDB) to develop an evolutionary model based on protein secondary structure. The approach follows the differences between discrete secondary structure states observed in modern proteins and those hypothesised in their immediate ancestors [1].

Based on this new evolutionary model, we implemented maximum likelihood-based phylogenetic inference tools to reconstruct ancestral secondary structure. The predictive accuracy from the use of the evolutionary model surpasses that of structural comparative modelling and sequence-based prediction methods; the reconstruction extracts information not available from modern structures or the ancestral protein sequences alone [3,4,5]. Based on a phylogenetic analysis of a sequence-diverse protein family, we showed that the model has the capacity to highlight relationships that are evolutionarily rooted in structure and not evident in sequence-based phylogenetic analysis.

Supplementary data and software for Evolutionary model of protein secondary structure capable of revealing new biological relationships are available from:

EvoluSec on GitHub

The original files were previously hosted on CloudStor. CloudStor was discontinued and decommissioned at the end of 2023, so the obsolete CloudStor download links have been removed.

ASSR requirement: Ancestral secondary structure reconstruction requires MATLAB 8.2 (R2013b) or later.
Feedback and questions: Contact the author.

Dayhoff M, Schwartz R, and Orcutt B (1978). A model of evolutionary change in proteins. In: Atlas of Protein Sequence and Structure, vol. 5, pp. 345–352. National Biomedical Research Foundation, Silver Spring, MD.
Ve T, Williams SJ, and Kobe B (2015). Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains. Apoptosis 20(2):250–261.
Clifton BE and Jackson CJ (2016). Ancestral protein reconstruction yields insights into adaptive evolution of binding specificity in solute-binding proteins. Cell Chemical Biology 23(2):236–245.
Hudson WH, Kossmann BR, de Vera IM, Chuo SW, Weikum ER, Eick GN, Thornton JW, Ivanov IN, Kojetin DJ, and Ortlund EA (2016). Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space. Proceedings of the National Academy of Sciences of the United States of America 113(2):326–331.
Wilson C, Agafonov RV, Hoemberger M, Kutter S, Zorba A, Halpin J, Buosi V, Otten R, Waterman D, Theobald DL, and Kern D (2015). Using ancient protein kinases to unravel a modern cancer drug's mechanism. Science 347(6224):882–886.

Evolu-sec was subsequently applied to analyse the structural divergence of Toll/interleukin-1 receptor domains, including the plant RUN1 TIR domain and human SARM1 TIR domain. The results were published in:

NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science 365(6455):793 (2019). DOI: 10.1126/science.aax1911

This page provides higher-resolution versions of figures included in the supplementary dataset for the article.

Figure 1. Unrooted phylogenetic tree of proteins containing TIR domains and structurally related domains. The tree includes 114 proteins from the intersection of DALI searches on human SARM1 TIR and plant RUN1 TIR. Only non-redundant proteins with structures at 4 Å resolution or better and superpositions covering at least 125 residues were used. Numbers on branches are standard bootstrap values based on 100 resamplings. Subtrees are coloured by kingdom and broad function and annotated with Gene Ontology terms statistically enriched for each group. Each leaf specifies PDB and UniProt identifiers, protein and gene names, the absolute number of mutated amino acids, and the ratio of residues missing from the structure relative to the protein sequence.

Figure 2. Alternative visualisation of Figure 1. Red, brown, green, blue, and purple tips represent mammalian TIR domains, bacterial TIR domains, plant TIR domains, enzymes, and response regulatory domains, respectively. The star and circle identify the plant RUN1 TIR and human SARM1 TIR structures, respectively.

Lai, Jhih-Siang. Protein structural phylogeny, a missing chapter in molecular evolutionary biology. PhD thesis, School of Chemistry and Molecular Biosciences, The University of Queensland, 2020. DOI: 10.14264/uql.2020.984

Jhih-Siang Lai's contributions to NAD+ cleavage activity by animal and plant TIR domains in cell death pathways included the article's “Bioinformatic analysis of TIR domains” section:

Writing the section.
Collecting and annotating data for the bioinformatics analysis.
Preparing figures for the section and supplementary information.
Developing the scientific concept and analysis design.

The “Bioinformatic analysis of TIR domains” section was also incorporated into Chapter 4 of Jhih-Siang Lai's PhD thesis.

Space limitations in Science meant that the published article could not describe these contributions in full. The PhD thesis documents the work in greater detail, including the methodology and process used to construct the structural phylogenetic tree of TIR domains.

The thesis was examined through The University of Queensland's formal doctoral examination process and reviewed by independent expert examiners. It therefore provides additional documentation of the research contributions and methodological work that could not be fully elaborated in the journal article.