AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research

Olsvik, Hallvard Lauritz; Johansen, Terje

doi:10.1371/journal.pbio.3002002

Cited by 4 publications

(3 citation statements)

References 10 publications

(14 reference statements)

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“…Despite the availability of experimental structures for 5-HT7R/Gs and CDK5/ p25 complexes (PDB ID: 7XTC [48] and 1H4L [49], respectively) direct protein-protein docking of CDK5 to 5-HT7R is complicated by the absence of a resolved structure for the ICL3, as well as any homologous fragments to model it. The structural prediction algorithm AlphaFold-multimer [50] has shown promising results in predicting the structures of protein complexes [20,[51][52][53], greatly surpassing the accuracy of protein docking [54]. Therefore, we employed the freely available platform ColabFold [19], which combines the AlphaFold2 algorithm with MMseqs2 sequence alignment.…”

Section: Computational Prediction Of the 5-ht7r/cdk5 Interaction Inte...mentioning

confidence: 99%

“…B Scheme depicts amino acid residues within m5-HT7R ICL3 and CDK5 αC-helix proposed to be involved in m5-HT7R/CDK5 interaction interface. C. Scheme depicts amino acid residues within α5 and α6 p25 domains and CDK5 αC-helix involved in formation of interaction interface (based on X-ray crystal structure 1H4L[53]. The α-helixes are shown as ovals and β-sheets as parallelograms.…”

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confidence: 99%

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Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

Ackmann,

Brüge,

Gotina

et al. 2024

Cell Commun Signal

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Background Multiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology. Methods Using biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex. Results We demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model. Conclusions Our results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer’s disease.

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Section: Computational Prediction Of the 5-ht7r/cdk5 Interaction Inte...mentioning

confidence: 99%

mentioning

confidence: 99%

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

Ackmann,

Brüge,

Gotina

et al. 2024

Cell Commun Signal

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“…AF-M was trained using five distinct regimens, yielding five models, each of which makes a structure prediction. Many groups are now using AF-M to uncover novel PPIs on the scale of pathways and organisms [12][13][14][15][16][17][18][19] . While many studies have examined AF-M's ability to correctly model individual protein complexes and predict structures for complexes in curated PPI databases [20][21][22] , there has been considerably less focus on finding systematic ways to separate true from false interactions in large-scale unbiased screens.…”

Section: Introductionmentioning

confidence: 99%

Predictomes: A classifier-curated database of AlphaFold-modeled protein-protein interactions

Schmid,

Walter

2024

Preprint

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Protein-protein interactions (PPIs) are ubiquitous in biology, yet a comprehensive structural characterization of the PPIs underlying biochemical processes is lacking. Although AlphaFold-Multimer (AF-M) has the potential to fill this knowledge gap, standard AF-M confidence metrics do not reliably separate relevant PPIs from an abundance of false positive predictions. To address this limitation, we used machine learning on well curated datasets to train a Structure Prediction and Omics informed Classifier called SPOC that shows excellent performance in separating true and false PPIs, including in proteome-wide screens. We applied SPOC to an all-by-all matrix of nearly 300 human genome maintenance proteins, generating ~40,000 predictions that can be viewed at predictomes.org, where users can also score their own predictions with SPOC. High confidence PPIs discovered using our approach suggest novel hypotheses in genome maintenance. Our results provide a framework for interpreting large scale AF-M screens and help lay the foundation for a proteome-wide structural interactome.

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Intercellular mitochondrial component transfer triggers ischemic cardiac fibrosis

Zhang¹,

Hao²,

Wang³

et al. 2023

Science Bulletin

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AlphaFold-multimer predicts ATG8 protein binding motifs crucial for autophagy research

Abstract: In this issue of PLOS Biology , Ibrahim and colleagues demonstrate how AlphaFold-multimer, an artificial intelligence–based structure prediction tool, can be used to identify sequence motifs binding to the ATG8 family of proteins central to autophagy.

Cited by 4 publications

References 10 publications

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

Predictomes: A classifier-curated database of AlphaFold-modeled protein-protein interactions

Intercellular mitochondrial component transfer triggers ischemic cardiac fibrosis

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