Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity
Signal transduction proteins are often multi-domain proteins that arose through the fusion of previously independent proteins. How such a change in the spatial arrangement of proteins impacts their evolution and the selective pressures acting on individual residues is largely unknown. We explored th...
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| Format: | Article |
| Language: | en_US |
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Wiley Blackwell
2014
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| Online Access: | http://hdl.handle.net/1721.1/86127 https://orcid.org/0000-0002-8288-7607 |
| _version_ | 1811089670837108736 |
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| author | Ashenberg, Orr Snow, Hana R. Skerker, Jeffrey M. Capra, Emily Jordan Perchuk, Barrett Seid, Charlotte Allen Laub, Michael T |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ashenberg, Orr Snow, Hana R. Skerker, Jeffrey M. Capra, Emily Jordan Perchuk, Barrett Seid, Charlotte Allen Laub, Michael T |
| author_sort | Ashenberg, Orr |
| collection | MIT |
| description | Signal transduction proteins are often multi-domain proteins that arose through the fusion of previously independent proteins. How such a change in the spatial arrangement of proteins impacts their evolution and the selective pressures acting on individual residues is largely unknown. We explored this problem in the context of bacterial two-component signalling pathways, which typically involve a sensor histidine kinase that specifically phosphorylates a single cognate response regulator. Although usually found as separate proteins, these proteins are sometimes fused into a so-called hybrid histidine kinase. Here, we demonstrate that the isolated kinase domains of hybrid kinases exhibit a dramatic reduction in phosphotransfer specificity in vitro relative to canonical histidine kinases. However, hybrid kinases phosphotransfer almost exclusively to their covalently attached response regulator domain, whose effective concentration exceeds that of all soluble response regulators. These findings indicate that the fused response regulator in a hybrid kinase normally prevents detrimental cross-talk between pathways. More generally, our results shed light on how the spatial properties of signalling pathways can significantly affect their evolution, with additional implications for the design of synthetic signalling systems. |
| first_indexed | 2024-09-23T14:22:54Z |
| format | Article |
| id | mit-1721.1/86127 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:22:54Z |
| publishDate | 2014 |
| publisher | Wiley Blackwell |
| record_format | dspace |
| spelling | mit-1721.1/861272022-09-29T09:04:23Z Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity Ashenberg, Orr Snow, Hana R. Skerker, Jeffrey M. Capra, Emily Jordan Perchuk, Barrett Seid, Charlotte Allen Laub, Michael T Massachusetts Institute of Technology. Department of Biology Laub, Michael T. Capra, Emily Jordan Perchuk, Barrett Ashenberg, Orr Seid, Charlotte Allen Snow, Hana R. Laub, Michael T. Signal transduction proteins are often multi-domain proteins that arose through the fusion of previously independent proteins. How such a change in the spatial arrangement of proteins impacts their evolution and the selective pressures acting on individual residues is largely unknown. We explored this problem in the context of bacterial two-component signalling pathways, which typically involve a sensor histidine kinase that specifically phosphorylates a single cognate response regulator. Although usually found as separate proteins, these proteins are sometimes fused into a so-called hybrid histidine kinase. Here, we demonstrate that the isolated kinase domains of hybrid kinases exhibit a dramatic reduction in phosphotransfer specificity in vitro relative to canonical histidine kinases. However, hybrid kinases phosphotransfer almost exclusively to their covalently attached response regulator domain, whose effective concentration exceeds that of all soluble response regulators. These findings indicate that the fused response regulator in a hybrid kinase normally prevents detrimental cross-talk between pathways. More generally, our results shed light on how the spatial properties of signalling pathways can significantly affect their evolution, with additional implications for the design of synthetic signalling systems. National Science Foundation (U.S.) (CAREER Award) National Science Foundation (U.S.). Graduate Research Fellowship Program 2014-04-11T19:17:33Z 2014-04-11T19:17:33Z 2012-11 2012-10 Article http://purl.org/eprint/type/JournalArticle 0950382X 1365-2958 http://hdl.handle.net/1721.1/86127 Capra, Emily J., Barrett S. Perchuk, Orr Ashenberg, Charlotte A. Seid, Hana R. Snow, Jeffrey M. Skerker, and Michael T. Laub. “Spatial Tethering of Kinases to Their Substrates Relaxes Evolutionary Constraints on Specificity.” Molecular Microbiology 86, no. 6 (December 2012): 1393–1403. https://orcid.org/0000-0002-8288-7607 en_US http://dx.doi.org/10.1111/mmi.12064 Molecular Microbiology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley Blackwell Laub via Courtney Crummett |
| spellingShingle | Ashenberg, Orr Snow, Hana R. Skerker, Jeffrey M. Capra, Emily Jordan Perchuk, Barrett Seid, Charlotte Allen Laub, Michael T Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title | Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title_full | Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title_fullStr | Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title_full_unstemmed | Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title_short | Spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| title_sort | spatial tethering of kinases to their substrates relaxes evolutionary constraints on specificity |
| url | http://hdl.handle.net/1721.1/86127 https://orcid.org/0000-0002-8288-7607 |
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