A kinetic mechanism for enhanced selectivity of membrane transport
| Autor: | Michael A. Lee, Michael Grabe, Daniel M. Zuckerman, August George, Paola Bisignano, John M. Rosenberg |
|---|---|
| Přispěvatelé: | Schlessinger, Avner |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytoplasm Physiology Toxicology Pathology and Laboratory Medicine Biochemistry Transport Pathway Mathematical Sciences Substrate Specificity Database and Informatics Methods 0302 clinical medicine Models Medicine and Health Sciences Toxins Synport Proteins Database Searching Biology (General) Membrane potential Ecology Organic Compounds Chemistry Monosaccharides Biological Sciences Electrophysiology Membrane Computational Theory and Mathematics 5.1 Pharmaceuticals Modeling and Simulation Physical Sciences Cellular Structures and Organelles Development of treatments and therapeutic interventions Detoxification Research Article Protein Binding QH301-705.5 Bioinformatics Toxic Agents Carbohydrates Molecular Dynamics Simulation Research and Analysis Methods Membrane Potential Models Biological 03 medical and health sciences Cellular and Molecular Neuroscience Sodium-Glucose Transporter 1 Information and Computing Sciences Genetics Humans Sugar transporter Binding site Molecular Biology Ecology Evolution Behavior and Systematics Binding Sites Organic Chemistry Chemical Compounds Biology and Life Sciences Galactose Proteins Membrane Transport Proteins Computational Biology Biological Transport Cell Biology Membrane transport Biological Kinetics 030104 developmental biology Docking (molecular) Biophysics Generic health relevance Extracellular Space 030217 neurology & neurosurgery |
| Zdroj: | PLoS computational biology, vol 16, iss 7 PLoS Computational Biology, Vol 16, Iss 7, p e1007789 (2020) PLoS Computational Biology |
| Popis: | 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. Author summary There is an important group of proteins, secondary active transporters, that are integral parts of membranes and that act as molecular pumps to move specific molecules, often referred to as cargo, across those membranes. This is an active process that typically exploits the energy inherent in the ionic gradients cells maintain across their membranes. Many transporters bind their cargos weakly because this is a physical requirement for rapid transport and this creates a problem that they would then fail to discriminate between the correct cargo and chemically similar molecules that would have a harmful effect if transported. Here, we explore the hypothesis that this discrimination can be enhanced by biochemical processes known in the literature as “proofreading” and/or “editing”. This exploration includes the expansion of an established kinetic model of a known transporter from V. parahaemolyticus (vSGLT) that transports sugars; mathematical analysis of the expanded model; numerical solution of the differential equations at the core of the expanded model; and a combination of data-base searches and molecular docking studies that establish the existence of toxic molecules sufficiently similar to the target cargo that they could be transported by vSGLT. We conclude that proofreading/editing is a plausible addition to the repertoire of secondary active transporters that would resolve the discrimination conundrum described above. We also note that the specifics of the model reported here reveal an interesting aspect of proofreading/editing behavior (unbounded selectivity) that, to our knowledge, has not been reported previously. |
| Databáze: | OpenAIRE |
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