The robustness of proofreading to crowding-induced pseudo-processivity in the MAPK pathway
Double phosphorylation of protein kinases is a common feature of signalling cascades. This motif may reduce cross-talk between signalling pathways, as the second phosphorylation site allows for proofreading, especially when phosphorylation is distributive rather than processive. Recent studies sugge...
| Main Authors: | , |
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| Format: | Journal article |
| Published: |
2014
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| _version_ | 1826295252137279488 |
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| author | Ouldridge, T Wolde, P |
| author_facet | Ouldridge, T Wolde, P |
| author_sort | Ouldridge, T |
| collection | OXFORD |
| description | Double phosphorylation of protein kinases is a common feature of signalling cascades. This motif may reduce cross-talk between signalling pathways, as the second phosphorylation site allows for proofreading, especially when phosphorylation is distributive rather than processive. Recent studies suggest that phosphorylation can be `pseudo-processive' in the crowded cellular environment, as rebinding after the first phosphorylation is enhanced by slow diffusion. Here, we use a simple model with unsaturated reactants to show that specificity for one substrate over another drops as rebinding increases and pseudo-processive behavior becomes possible. However, this loss of specificity with increased rebinding is typically also observed if two distinct enzyme species are required for phosphorylation, i.e. when the system is necessarily distributive. Thus the loss of specificity is due to an intrinsic reduction in selectivity with increased rebinding, which benefits inefficient reactions, rather than pseudo-processivity itself. We also show that proofreading can remain effective when the intended signalling pathway exhibits high levels of rebinding-induced pseudo-processivity, unlike other proposed advantages of the dual phosphorylation motif. |
| first_indexed | 2024-03-07T03:58:10Z |
| format | Journal article |
| id | oxford-uuid:c397681d-8a81-4c8e-849d-0fd13fe684bf |
| institution | University of Oxford |
| last_indexed | 2024-03-07T03:58:10Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:c397681d-8a81-4c8e-849d-0fd13fe684bf2022-03-27T06:17:33ZThe robustness of proofreading to crowding-induced pseudo-processivity in the MAPK pathwayJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c397681d-8a81-4c8e-849d-0fd13fe684bfSymplectic Elements at Oxford2014Ouldridge, TWolde, PDouble phosphorylation of protein kinases is a common feature of signalling cascades. This motif may reduce cross-talk between signalling pathways, as the second phosphorylation site allows for proofreading, especially when phosphorylation is distributive rather than processive. Recent studies suggest that phosphorylation can be `pseudo-processive' in the crowded cellular environment, as rebinding after the first phosphorylation is enhanced by slow diffusion. Here, we use a simple model with unsaturated reactants to show that specificity for one substrate over another drops as rebinding increases and pseudo-processive behavior becomes possible. However, this loss of specificity with increased rebinding is typically also observed if two distinct enzyme species are required for phosphorylation, i.e. when the system is necessarily distributive. Thus the loss of specificity is due to an intrinsic reduction in selectivity with increased rebinding, which benefits inefficient reactions, rather than pseudo-processivity itself. We also show that proofreading can remain effective when the intended signalling pathway exhibits high levels of rebinding-induced pseudo-processivity, unlike other proposed advantages of the dual phosphorylation motif. |
| spellingShingle | Ouldridge, T Wolde, P The robustness of proofreading to crowding-induced pseudo-processivity in the MAPK pathway |
| title | The robustness of proofreading to crowding-induced pseudo-processivity
in the MAPK pathway |
| title_full | The robustness of proofreading to crowding-induced pseudo-processivity
in the MAPK pathway |
| title_fullStr | The robustness of proofreading to crowding-induced pseudo-processivity
in the MAPK pathway |
| title_full_unstemmed | The robustness of proofreading to crowding-induced pseudo-processivity
in the MAPK pathway |
| title_short | The robustness of proofreading to crowding-induced pseudo-processivity
in the MAPK pathway |
| title_sort | robustness of proofreading to crowding induced pseudo processivity in the mapk pathway |
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