Leveraging protein structural information to improve variant effect prediction

Current Opinion in Structural Biology, Journal Year: 2025, Volume and Issue: 92, P. 103023 - 103023

Published: Feb. 22, 2025

Despite massive sequencing efforts, understanding the difference between human pathogenic and benign variants remains a challenge. Computational variant effect predictors (VEPs) have emerged as essential tools for assessing impact of genetic variants, although their performance varies. Initially, sequence-based methods dominated field, but recent advances, particularly in protein structure prediction technologies like AlphaFold, led to an increased utilization structural information by VEPs aimed at scoring missense variants. This review highlights progress integrating into VEPs, showcasing novel models such AlphaMissense, PrimateAI-3D, CPT-1 that demonstrate improved evaluation. Structural data offers more interpretability, especially non-loss-of-function provides insights complex interactions vivo. As field utilizing biomolecular structures will be pivotal future VEP development, with breakthroughs protein-ligand protein-nucleic acid offering new avenues.

Language: Английский

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Mutational biases favor complexity increases in protein interaction networks after gene duplication

Molecular Systems Biology, Journal Year: 2024, Volume and Issue: 20(5), P. 549 - 572

Published: March 18, 2024

Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At molecular level, one example heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate evolution homodimers heterodimers duplication using distributions mutational effects inferred from available protein structures. We keep specific activity each dimer identical, so their concentrations drift neutrally new functions. show that for more than 60% tested structures, relative concentration heteromer increases time due biases favor heterodimer. However, allowing on synthesis rates differences in homo- limit or reverse observed bias toward heterodimers. Our results accumulation complex quaternary structures under neutral evolution, selection would be needed this tendency.

Language: Английский

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Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(8), P. e0307312 - e0307312

Published: Aug. 22, 2024

Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which diseases exert their effects is often experimentally challenging resource intensive, but essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated conventional gene therapy, whereas DN GOF may require editing or targeting small molecules. Moreover, pathogenic missense mutations act difficult identify than those using nearly all currently available variant effect predictors. Here, we introduce tripartite statistical model made up of support vector machine binary classifiers trained predict whether human protein coding genes likely associated with DN, GOF, molecular disease We test utility predictions examining biologically clinically meaningful properties known Our results strongly models able generalise on unseen data offer insight into functional attributes proteins different hope our will serve as springboard researchers studying novel variants uncertain clinical significance, guiding interpretation strategies experimental characterisation. Predictions UniProt reference proteome at https://osf.io/z4dcp/ .

Language: Английский

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Ciliopathy-associated missense mutations in IFT140 are tolerated by the inherent resilience of the IFT machinery

Molecular & Cellular Proteomics, Journal Year: 2025, Volume and Issue: unknown, P. 100916 - 100916

Published: Jan. 1, 2025

Language: Английский

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Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 26, 2024

Abstract Advances in structure determination and computational modelling are enabling us to study the protein structural context of human genetic variants at an unprecedented scale. Here, we investigate millions cancer-associated missense mutations terms their locations predicted perturbative effects. We find that, while cancer-driving have properties similar other known disease-causing mutations, this is obscured by abundance passenger cancer sequencing datasets. Nevertheless, considering collective level individual proteins, identify distinct mutational signatures associated with tumour suppressors oncogenes. Tumour enriched structurally damaging consistent loss-of-function mechanisms. In contrast, oncogene tend be mild, reflecting selection for gain-of-function driver against mutations. Although oncogenes difficult distinguish from genes no role using only damage, that alternate metric based on clustering three-dimensional space highly predictive oncogenes, particularly when mutation recurrence considered. These observations allow novel candidate speculate about molecular roles, which expect general utility analysis data.

Language: Английский

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Benefits of co‐translational complex assembly for cellular fitness

BioEssays, Journal Year: 2023, Volume and Issue: 45(5)

Published: March 14, 2023

Complexes of two or more proteins form many, if not most, the intracellular "machines" that execute physical and chemical work, transmit information. can from stochastic post-translational interactions fully formed proteins, but recent attention has shifted to co-translational in which most common mechanism involves binding a mature constituent an incomplete polypeptide emerging translating ribosome. Studies yeast have revealed during formation multiple major complexes, together with mammalian cell studies, suggest widespread utilization mechanism. These translation-dependent involve single mRNA templates, be uni- bi-directional, use multi-protein sub-complexes as component. Here, we discuss benefits complex assembly including accuracy efficiency, overcoming hidden interfaces, localized hierarchical assembly, reduction orphan protein degradation, toxicity, dominant-negative pathogenesis, all serving improve fitness.

Language: Английский

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Proteome-scale prediction of molecular mechanisms underlying dominant genetic diseases

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 8, 2023

Abstract Many dominant genetic disorders result from protein-altering mutations, acting primarily through dominant-negative (DN), gain-of-function (GOF), and loss-of-function (LOF) mechanisms. Deciphering the mechanisms by which diseases exert their effects is often experimentally challenging resource intensive, but essential for developing appropriate therapeutic approaches. Diseases that arise via a LOF mechanism are more amenable to be treated conventional gene therapy, whereas DN GOF may require editing or targeting small molecules. Moreover, pathogenic missense mutations act difficult identify than those using nearly all currently available variant effect predictors. Here, we introduce tripartite statistical model made up of support vector machine binary classifiers trained predict whether human protein-coding genes likely associated with DN, GOF, molecular disease We test utility predictions examining biologically clinically meaningful properties known Our results strongly models able generalise on unseen data offer insight into functional attributes proteins different hope our will serve as springboard researchers studying novel variants uncertain clinical significance, guiding interpretation strategies experimental characterisation. Predictions UniProt reference proteome at https://osf.io/z4dcp/ .

Language: Английский

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Orchestrated centers for the production of proteins or “translation factories”

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2024, Volume and Issue: 15(4)

Published: July 1, 2024

The mechanics of how proteins are generated from mRNA is increasingly well understood. However, much less known about protein production coordinated and orchestrated within the crowded intracellular environment, especially in eukaryotic cells. Recent studies suggest that localized sites exist for specific proteins. These have been termed "translation factories" roles complex formation, localization, inheritance, translation regulation postulated. In this article, we review evidence supporting at these sites, details their mechanism likely functional significance. Finally, consider key uncertainties regarding elusive structures This article categorized under: Translation > Mechanisms RNA Export Localization Regulation.

Language: Английский

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Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: April 6, 2024

Abstract Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of white matter in brain. The caused a deficiency cytosolic aspartoacylase (ASPA) enzyme, which catalyzes hydrolysis N-acetyl-aspartate (NAA), abundant brain metabolite, into aspartate acetate. On physiological level, mechanism pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At molecular recent studies have shown that most linked ASPA gene variants lead to structural destabilization subsequent proteasomal degradation protein variants, accordingly should general be considered misfolding disorder. Here, we comprehensively summarize cell biology ASPA, particular focus on disease-linked pathophysiology disease. We highlight importance high-throughput technologies computational prediction tools for making genotype–phenotype predictions as await results ongoing trials therapy

Language: Английский

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Hallmarks and evolutionary drivers of cotranslational protein complex assembly

FEBS Journal, Journal Year: 2023, Volume and Issue: 291(16), P. 3557 - 3567

Published: May 19, 2023

Recent discoveries have highlighted the prevalence of cotranslational assembly in proteomes, revealing a range mechanisms that enables protein complex subunits on ribosome. Structural analyses uncovered emergent properties may inherently control whether subunit undergoes assembly. However, evolutionary paths yielded such complexes over an extended timescale remain largely unclear. In this review, we reflect historical experiments contributed to field, including breakthroughs made possible proteome-wide detection assembly, and technical challenges yet be overcome. We introduce simple framework encapsulates hallmarks discuss how results from new are shaping our view mechanistic, structural factors driving phenomenon.

Language: Английский

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