The properties of human disease mutations at protein interfaces.
The assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consider...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-02-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009858&type=printable |
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| author | Benjamin J Livesey Joseph A Marsh |
| author_facet | Benjamin J Livesey Joseph A Marsh |
| author_sort | Benjamin J Livesey |
| collection | DOAJ |
| description | The assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consideration for how this varies between different types of interfaces. Here we investigate the properties of human pathogenic and putatively benign missense variants at homomeric (isologous and heterologous), heteromeric, DNA, RNA and other ligand interfaces, and at different regions in proteins with respect to those interfaces. We find that different types of interfaces vary greatly in their propensity to be associated with pathogenic mutations, with homomeric heterologous and DNA interfaces being particularly enriched in disease. We also find that residues that do not directly participate in an interface, but are close in three-dimensional space, show a significant disease enrichment. Finally, we observe that mutations at different types of interfaces tend to have distinct property changes when undergoing amino acid substitutions associated with disease, and that this is linked to substantial variability in their identification by computational variant effect predictors. |
| format | Article |
| id | doaj-art-dc37a64daa9d48ccb4954d5a0fbab145 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-dc37a64daa9d48ccb4954d5a0fbab1452025-08-20T02:23:18ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582022-02-01182e100985810.1371/journal.pcbi.1009858The properties of human disease mutations at protein interfaces.Benjamin J LiveseyJoseph A MarshThe assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consideration for how this varies between different types of interfaces. Here we investigate the properties of human pathogenic and putatively benign missense variants at homomeric (isologous and heterologous), heteromeric, DNA, RNA and other ligand interfaces, and at different regions in proteins with respect to those interfaces. We find that different types of interfaces vary greatly in their propensity to be associated with pathogenic mutations, with homomeric heterologous and DNA interfaces being particularly enriched in disease. We also find that residues that do not directly participate in an interface, but are close in three-dimensional space, show a significant disease enrichment. Finally, we observe that mutations at different types of interfaces tend to have distinct property changes when undergoing amino acid substitutions associated with disease, and that this is linked to substantial variability in their identification by computational variant effect predictors.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009858&type=printable |
| spellingShingle | Benjamin J Livesey Joseph A Marsh The properties of human disease mutations at protein interfaces. PLoS Computational Biology |
| title | The properties of human disease mutations at protein interfaces. |
| title_full | The properties of human disease mutations at protein interfaces. |
| title_fullStr | The properties of human disease mutations at protein interfaces. |
| title_full_unstemmed | The properties of human disease mutations at protein interfaces. |
| title_short | The properties of human disease mutations at protein interfaces. |
| title_sort | properties of human disease mutations at protein interfaces |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1009858&type=printable |
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