Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?
Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved..
Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of the 2134 neutral variants are structurally damaging. Importantly, similar results are obtained when 1052 structures predicted using Phyre2 algorithm were used, even when the model shares low (<40%) sequence identity to the template. Thus, structure-based analysis of the effects of missense variants can be effectively applied to homology models. Our in-house pipeline, Missense3D, for structurally assessing missense variants was made available at http://www.sbg.bio.ic.ac.uk/~missense3d.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:431 |
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| Enthalten in: |
Journal of molecular biology - 431(2019), 11 vom: 17. Mai, Seite 2197-2212 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ittisoponpisan, Sirawit [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 30.03.2020 Date Revised 09.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jmb.2019.04.009 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM296160202 |
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| 500 | |a Date Revised 09.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of the 2134 neutral variants are structurally damaging. Importantly, similar results are obtained when 1052 structures predicted using Phyre2 algorithm were used, even when the model shares low (<40%) sequence identity to the template. Thus, structure-based analysis of the effects of missense variants can be effectively applied to homology models. Our in-house pipeline, Missense3D, for structurally assessing missense variants was made available at http://www.sbg.bio.ic.ac.uk/~missense3d | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Phyre2 protein structure prediction | |
| 650 | 4 | |a missense variants | |
| 650 | 4 | |a protein structure prediction | |
| 650 | 4 | |a structure-based prediction | |
| 650 | 4 | |a variant effect prediction | |
| 650 | 7 | |a Proteins |2 NLM | |
| 700 | 1 | |a Islam, Suhail A |e verfasserin |4 aut | |
| 700 | 1 | |a Khanna, Tarun |e verfasserin |4 aut | |
| 700 | 1 | |a Alhuzimi, Eman |e verfasserin |4 aut | |
| 700 | 1 | |a David, Alessia |e verfasserin |4 aut | |
| 700 | 1 | |a Sternberg, Michael J E |e verfasserin |4 aut | |
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