On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Longo, Liam M.; Jabłońska, Jagoda; Vyas, Pratik; Kanade, Manil; Kolodny, Rachel; Ben‐Tal, Nir; Tawfik, Dan S.

doi:10.7554/elife.64415

Cited by 76 publications

(132 citation statements)

References 45 publications

(90 reference statements)

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“…Finally, another tantalizing evolutionary link we have identified connects the two most ancient and diverse lineages of Rossmann-like and P-loop NTPases and is analyzed in detail separately ( Longo et al. 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Bridging Themes: Short Protein Segments Found in Different Architectures

Kolodny

Nepomnyachiy

Tawfik

et al. 2021

Molecular Biology and Evolution

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The vast majority of theoretically possible polypeptide chains do not fold, let alone confer function. Hence, protein evolution from preexisting building blocks has clear potential advantages over ab initio emergence from random sequences. In support of this view, sequence similarities between different proteins is generally indicative of common ancestry, and we collectively refer to such homologous sequences as ‘themes’. At the domain level, sequence homology is routinely detected. However, short themes which are segments, or fragments of intact domains, are particularly interesting because they may provide hints about the emergence of domains, as opposed to divergence of preexisting domains, or their mixing-and-matching to form multi-domain proteins. Here we identified 525 representative short themes, comprising 20-to-80 residues, that are unexpectedly shared between domains considered to have emerged independently. Among these ‘bridging themes’ are ones shared between the most ancient domains, e.g., Rossmann, P-loop NTPase, TIM-barrel, Flavodoxin, and Ferredoxin-like. We elaborate on several particularly interesting cases, where the bridging themes mediate ligand binding. Ligand binding may have contributed to the stability and the plasticity of these building blocks, and to their ability to invade preexisting domains or serve as starting points for completely new domains.

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Section: Resultsmentioning

confidence: 99%

Bridging Themes: Short Protein Segments Found in Different Architectures

Kolodny

Nepomnyachiy

Tawfik

et al. 2021

Molecular Biology and Evolution

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“…The ATPase domain of a AAA+ module (referred to as Domain 1, see Figure 1A ) belongs to the much broader class of P-loop NTPases that also includes monomeric GTPases and oligomeric ATPases of the RecA and F-type ATPase families ( Erzberger and Berger, 2006 ; Iyer et al, 2004 ). These proteins share evolutionarily ancient Walker A and Walker B sequence motifs ( Cullmann et al, 1995 ; Guenther et al, 1997 ; Longo et al, 2020 ; Neuwald et al, 1999 ). Residues in the Walker A motif (residues 45–58 in the ATPase subunit of T4 clamp loader) form the P-loop that cradles the β and γ phosphate groups of the nucleotide.…”

Section: Introductionmentioning

confidence: 99%

Allosteric communication in DNA polymerase clamp loaders relies on a critical hydrogen-bonded junction

Subramanian

Gorday

Marcus

et al. 2021

eLife

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Clamp loaders are AAA+ ATPases that load sliding clamps onto DNA. We mapped the mutational sensitivity of the T4 bacteriophage sliding clamp and clamp loader by deep mutagenesis, and found that residues not involved in catalysis or binding display remarkable tolerance to mutation. An exception is a glutamine residue in the AAA+ module (Gln 118) that is not located at a catalytic or interfacial site. Gln 118 forms a hydrogen-bonded junction in a helical unit that we term the central coupler, because it connects the catalytic centers to DNA and the sliding clamp. A suppressor mutation indicates that hydrogen bonding in the junction is important, and molecular dynamics simulations reveal that it maintains rigidity in the central coupler. The glutamine-mediated junction is preserved in diverse AAA+ ATPases, suggesting that a connected network of hydrogen bonds that links ATP molecules is an essential aspect of allosteric communication in these proteins.

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“…In this work, we chose to showcase Protlego’s features on a biologically relevant example that has attracted the attention of many groups in the past: The relationship of the P-loop and Rossmann folds ( Longo et al , 2020 ) . By fetching hits from Fuzzle, we obtained a total of 1737 domains of these two folds.…”

Section: Discussionmentioning

confidence: 99%

Protlego: a Python package for the analysis and design of chimeric proteins

2021

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Motivation Duplication and recombination of protein fragments have led to the highly diverse protein space that we observe today. By mimicking this natural process, the design of protein chimeras via fragment recombination has proven experimentally successful and has opened a new era for the design of customizable proteins. The in silico building of structural models for these chimeric proteins, however, remains a manual task that requires a considerable degree of expertise and is not amenable for high-throughput studies. Energetic and structural analysis of the designed proteins often require the use of several tools, each with their unique technical difficulties and available in different programming languages or web servers. Results We implemented a Python package that enables automated, high-throughput design of chimeras and their structural analysis. First, it fetches evolutionarily conserved fragments from a built-in database (also available at fuzzle.uni-bayreuth.de). These relationships can then be represented via networks or further selected for chimera construction via recombination. Designed chimeras or natural proteins are then scored and minimized with the Charmm and Amber forcefields and their diverse structural features can be analyzed at ease. Here, we showcase Protlego’s pipeline by exploring the relationships between the P-loop and Rossmann superfolds, building and characterizing their offspring chimeras. We believe that Protlego provides a powerful new tool for the protein design community. Availability and implementation Protlego runs on the Linux platform and is freely available at (https://hoecker-lab.github.io/protlego/) with tutorials and documentation. Supplementary information Supplementary data are available at Bioinformatics online.

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On the emergence of P-Loop NTPase and Rossmann enzymes from a Beta-Alpha-Beta ancestral fragment

Cited by 76 publications

References 45 publications

Bridging Themes: Short Protein Segments Found in Different Architectures

Bridging Themes: Short Protein Segments Found in Different Architectures

Allosteric communication in DNA polymerase clamp loaders relies on a critical hydrogen-bonded junction

Protlego: a Python package for the analysis and design of chimeric proteins

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