Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.
Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between th...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-04-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1010006 |
| _version_ | 1797959153212194816 |
|---|---|
| author | Nicholas J Ose Brandon M Butler Avishek Kumar I Can Kazan Maxwell Sanderford Sudhir Kumar S Banu Ozkan |
| author_facet | Nicholas J Ose Brandon M Butler Avishek Kumar I Can Kazan Maxwell Sanderford Sudhir Kumar S Banu Ozkan |
| author_sort | Nicholas J Ose |
| collection | DOAJ |
| description | Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease. |
| first_indexed | 2024-04-11T00:29:30Z |
| format | Article |
| id | doaj.art-6e2ba546c14d47ba9f054f2d9606ca48 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-11T00:29:30Z |
| publishDate | 2022-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-6e2ba546c14d47ba9f054f2d9606ca482023-01-08T05:30:40ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582022-04-01184e101000610.1371/journal.pcbi.1010006Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants.Nicholas J OseBrandon M ButlerAvishek KumarI Can KazanMaxwell SanderfordSudhir KumarS Banu OzkanMany pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.https://doi.org/10.1371/journal.pcbi.1010006 |
| spellingShingle | Nicholas J Ose Brandon M Butler Avishek Kumar I Can Kazan Maxwell Sanderford Sudhir Kumar S Banu Ozkan Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. PLoS Computational Biology |
| title | Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. |
| title_full | Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. |
| title_fullStr | Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. |
| title_full_unstemmed | Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. |
| title_short | Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants. |
| title_sort | dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants |
| url | https://doi.org/10.1371/journal.pcbi.1010006 |
| work_keys_str_mv | AT nicholasjose dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT brandonmbutler dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT avishekkumar dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT icankazan dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT maxwellsanderford dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT sudhirkumar dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants AT sbanuozkan dynamiccouplingofresidueswithinproteinsasamechanisticfoundationofmanyenigmaticpathogenicmissensevariants |