Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction

Sánchez‐Pulido, Luis; Ponting, Chris P.

doi:10.1016/j.jmb.2021.167106

Cited by 8 publications

(11 citation statements)

References 116 publications

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“…Protein structure is typically more conserved than primary sequence and better allows detection of diverged homologs ( Sanchez-Pulido and Ponting, 2021 ). Because the protein structure of MES-3 is not yet experimentally resolved, we used deep-learning driven protein structure prediction of both MES-3 and SUZ12 with Alphafold2 ( Jumper et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Caenorhabditis elegans MES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Snel¹,

Heuvel²,

Seidl³

2022

iScience

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Section: Resultsmentioning

confidence: 99%

Caenorhabditis elegans MES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Snel¹,

Heuvel²,

Seidl³

2022

iScience

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“…The here described similarities and differences between SUZ12 and MES-3 should facilitate further experiments to elucidate the specific mechanisms by which MES-3 acts in PRC2 in C. elegans. Our work joins a rapidly growing set of in silico predictions of previously undetected homologies made possible by unprecedented advances in deep-learning driven structure prediction 22,30 .…”

Section: Resultsmentioning

confidence: 97%

“…Protein structure is typically more conserved than primary sequence and better allows detection of diverged homologs 22 . Since the protein structure of MES-3 is not yet experimentally resolved, we used deep-learning driven protein structure prediction of both MES-3 and SUZ12 with Alphafold2 23 .…”

Section: Resultsmentioning

confidence: 99%

“…We capitalized on recent advantages on computational prediction approaches that enable to derive high-quality structures of protein monomers or multimers 23,24 , which enables to study protein function and evolution at unprecedented scale 22,30 . We demonstrate that MES-3 is a diverged ortholog of SUZ12, and that MES-3 may associate with MES-2, MES-6, and LIN-53, similar to the orthologous proteins in human PRC2.…”

Section: Limitation Of the Sudymentioning

confidence: 99%

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Caenorhabditis elegansMES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Snel

Heuvel

Seidl

2022

Preprint

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Polycomb Repressive Complex 2 (PRC2) catalyzes the mono-, di, and trimethylation of histone protein H3 on lysine 27 (H3K27). Trimethylation of H3K27 is strongly associated with transcriptionally silent chromatin and plays an important role in the regulation of cell identity and developmental gene expression. The functional core of PRC2 is highly conserved in animals and consists of four subunits (Fig. 1a). Notably, one of these subunits, SUZ12, has not been identified in the genetic model Caenorhabditis elegans, whereas C. elegans PRC2 contains the lineage-specific protein MES-3 (Fig. 1a). Here, we demonstrate that MES-3 is in fact a highly divergent ortholog of SUZ12. Unbiased sensitive sequence similarity searches uncovered consistent but insignificant reciprocal best matches between MES-3 and SUZ12, suggesting that these proteins could share a common evolutionary history. We substantiate this hypothesis by directly comparing the predicted structures of SUZ12 and MES-3, which revealed shared protein folds and residues of key domains. Thus, in agreement with the observations in previous genetic and biochemical studies, we here provide evidence that C. elegans, like other animals, contains a diverged yet evolutionary conserved core PRC2.

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“…AlphaFold 1 ( Senior et al, 2020 ) was introduced in CASP13 blind structure prediction competition in 2018. One of the key premises in structure prediction by AlphaFold 1 is that coevolving residues are likely to be located close to each other in a 3D structure of a protein Sanchez-Pulido and Ponting (2021) . The input of AlphaFold 1 is an amino acid sequence of the modeled protein.…”

Section: Introductionmentioning

confidence: 99%

Collective Variable for Metadynamics Derived From AlphaFold Output

Spiwok

Kurečka

Křenek

2022

Front. Mol. Biosci.

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AlphaFold is a neural network–based tool for the prediction of 3D structures of proteins. In CASP14, a blind structure prediction challenge, it performed significantly better than other competitors, making it the best available structure prediction tool. One of the outputs of AlphaFold is the probability profile of residue–residue distances. This makes it possible to score any conformation of the studied protein to express its compliance with the AlphaFold model. Here, we show how this score can be used to drive protein folding simulation by metadynamics and parallel tempering metadynamics. Using parallel tempering metadynamics, we simulated the folding of a mini-protein Trp-cage and β hairpin and predicted their folding equilibria. We observe the potential of the AlphaFold-based collective variable in applications beyond structure prediction, such as in structure refinement or prediction of the outcome of a mutation.

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Extending the Horizon of Homology Detection with Coevolution-based Structure Prediction

Abstract: Graphical abstract

Cited by 8 publications

References 116 publications

Caenorhabditis elegans MES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Caenorhabditis elegans MES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Caenorhabditis elegansMES-3 is a highly divergent ortholog of the canonical PRC2 component SUZ12

Collective Variable for Metadynamics Derived From AlphaFold Output

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