A kinetic mechanism for enhanced selectivity of membrane transport.
Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intr...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-07-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1007789 |
| _version_ | 1798029253020745728 |
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| author | Paola Bisignano Michael A Lee August George Daniel M Zuckerman Michael Grabe John M Rosenberg |
| author_facet | Paola Bisignano Michael A Lee August George Daniel M Zuckerman Michael Grabe John M Rosenberg |
| author_sort | Paola Bisignano |
| collection | DOAJ |
| description | Membrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this 'slip' mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a 'detoxification' mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development. |
| first_indexed | 2024-04-11T19:22:22Z |
| format | Article |
| id | doaj.art-8e548db78b314bef88a8ef4d85ce8354 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-11T19:22:22Z |
| publishDate | 2020-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-8e548db78b314bef88a8ef4d85ce83542022-12-22T04:07:17ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582020-07-01167e100778910.1371/journal.pcbi.1007789A kinetic mechanism for enhanced selectivity of membrane transport.Paola BisignanoMichael A LeeAugust GeorgeDaniel M ZuckermanMichael GrabeJohn M RosenbergMembrane transport is generally thought to occur via an alternating access mechanism in which the transporter adopts at least two states, accessible from two different sides of the membrane to exchange substrates from the extracellular environment and the cytoplasm or from the cytoplasm and the intracellular matrix of the organelles (only in eukaryotes). In recent years, a number of high resolution structures have supported this general framework for a wide class of transport molecules, although additional states along the transport pathway are emerging as critically important. Given that substrate binding is often weak in order to enhance overall transport rates, there exists the distinct possibility that transporters may transport the incorrect substrate. This is certainly the case for many pharmaceutical compounds that are absorbed in the gut or cross the blood brain barrier through endogenous transporters. Docking studies on the bacterial sugar transporter vSGLT reveal that many highly toxic compounds are compatible with binding to the orthosteric site, further motivating the selective pressure for additional modes of selectivity. Motivated by recent work in which we observed failed substrate delivery in a molecular dynamics simulation where the energized ion still goes down its concentration gradient, we hypothesize that some transporters evolved to harness this 'slip' mechanism to increase substrate selectivity and reduce the uptake of toxic molecules. Here, we test this idea by constructing and exploring a kinetic transport model that includes a slip pathway. While slip reduces the overall productive flux, when coupled with a second toxic molecule that is more prone to slippage, the overall substrate selectivity dramatically increases, suppressing the accumulation of the incorrect compound. We show that the mathematical framework for increased substrate selectivity in our model is analogous to the classic proofreading mechanism originally proposed for tRNA synthase; however, because the transport cycle is reversible we identified conditions in which the selectivity is essentially infinite and incorrect substrates are exported from the cell in a 'detoxification' mode. The cellular consequences of proofreading and membrane slippage are discussed as well as the impact on future drug development.https://doi.org/10.1371/journal.pcbi.1007789 |
| spellingShingle | Paola Bisignano Michael A Lee August George Daniel M Zuckerman Michael Grabe John M Rosenberg A kinetic mechanism for enhanced selectivity of membrane transport. PLoS Computational Biology |
| title | A kinetic mechanism for enhanced selectivity of membrane transport. |
| title_full | A kinetic mechanism for enhanced selectivity of membrane transport. |
| title_fullStr | A kinetic mechanism for enhanced selectivity of membrane transport. |
| title_full_unstemmed | A kinetic mechanism for enhanced selectivity of membrane transport. |
| title_short | A kinetic mechanism for enhanced selectivity of membrane transport. |
| title_sort | kinetic mechanism for enhanced selectivity of membrane transport |
| url | https://doi.org/10.1371/journal.pcbi.1007789 |
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