Abstract
Intracellular protein concentration gradients are generally thought to be unsustainable at steady-state due to diffusion. Here we show how protein concentration gradients can theoretically be sustained indefinitely through a relatively simple mechanism that couples diffusion to a spatially segregated kinase–phosphatase system. Although it is appreciated that such systems can theoretically give rise to phosphostate gradients, it has been assumed that they do not give rise to gradients in the total protein concentration. Here we show that this assumption does not hold if the two forms of protein have different diffusion coefficients. If, for example, the phosphorylated state binds selectively to a second larger protein or protein complex, then a steady-state gradient in total protein concentration will be created. We illustrate the principle with an analytical solution to the diffusion-reaction problem and by stochastic individual-based simulations using the Smoldyn program. We argue that protein gradients created in this way need to be considered in experiments using fluorescent probes and could in principle encode spatial information in the cytoplasm.
Similar content being viewed by others
Abbreviations
- A:
-
CheA
- Y:
-
CheY
- Yp, CheYp:
-
Phosphorylated CheY
- Z2 :
-
CheZ dimer
References
Andrews S. S., D. Bray. Stochastic simulation of chemical reactions with spatial resolution and single molecule detail. Phys. Biol. 1:137–151, 2004
Blat Y., M. Eisenbach. Phosphorylation-dependent binding of the chemotaxis signal molecule CheY to its phosphatase, CheZ. Biochemistry 33(4):902–906, 1994
Brown G. C., B. N. Kholodenko. Spatial gradients of cellular phospho-proteins. FEBS Lett 457(3):452–454, 1999
Cassimeris L. The oncoprotein 18/stathmin family of microtubule destabilizers. Curr. Opin. Cell Biol. 14(1):18–24, 2002
Caudron M., G. Bunt, P. Bastiaens, E. Karsenti. Spatial coordination of spindle assembly by chromosome-mediated signaling gradients. Science 309(5739):1373–1376, 2005
Cermelli S., Y. Guo, S. P. Gross, M. A. Welte. The lipid-droplet proteome reveals that droplets are a protein-storage depot. Curr. Biol. 16(18):1783–1795, 2006
Francis N. R., M. N. Levit, T. R. Shaikh, L. A. Melanson, J. B. Stock, D. J. DeRosier. Subunit organization in a soluble complex of tar, CheW, and CheA by electron microscopy. J. Biol. Chem. 277(39):36755–36759, 2002
Gardner M. K., C. G. Pearson, B. L. Sprague, T. R. Zarzar, K. Bloom, E. D. Salmon, and D. J. Odde. Tension-dependent regulation of microtubule dynamics at kinetochores can explain metaphase congression in yeast. Mol. Biol. Cell 16(8):3764–3775, 2005
Haugh J. M. Membrane-binding/modification model of signaling protein activation and analysis of its control by cell morphology. Biophys. J. 92(11):L93–L95, 2007
Jacobson K., J. Wojcieszyn. The translational mobility of substances within the cytoplasmic matrix. Proc. Natl. Acad. Sci. USA 81(21):6747–6751, 1984
Kalab P., A. Pralle, E. Y. Isacoff, R. Heald, K. Weis. Analysis of a RanGTP-regulated gradient in mitotic somatic cells. Nature 440(7084):697–701, 2006
Kalab P., K. Weis, R. Heald. Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 295(5564):2452–2456, 2002
Li M., G. L. Hazelbauer. Cellular stoichiometry of the components of the chemotaxis signaling complex. J. Bacteriol. 186(12):3687–3694, 2004
Lin A. C., C. E. Holt. Local translation and directional steering in axons. EMBO J 26(16):3729–3736, 2007
Lipkow K. Changing cellular location of CheZ predicted by molecular simulations. PLoS Comput. Biol. 2(4):e39.
Lipkow K., S. S. Andrews, D. Bray. Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli. J. Bacteriol. 187(1):45–53, 2005
Meyers J., J. Craig, D. J. Odde. Potential for control of signaling pathways via cell size and shape. Curr. Biol. 16(17):1685–1693, 2006
Nalbant P., L. Hodgson, V. Kraynov, A. Toutchkine, K. M. Hahn. Activation of endogenous Cdc42 visualized in living cells. Science 305(5690):1615–1619, 2004
Niethammer P., P. Bastiaens, E. Karsenti. Stathmin-tubulin interaction gradients in motile and mitotic cells. Science 303(5665):1862–1866, 2004
Odde D. Diffusion inside microtubules. Eur. Biophys. J. 27(5):514–520, 1998
Shrout A. L., D. J. Montefusco, R. M. Weis. Template-directed assembly of receptor signaling complexes. Biochemistry 42(46):13379–13385, 2003
Sourjik V. Receptor clustering and signal processing in E. coli chemotaxis. Trends Microbiol. 12(12):569–576, 2004
Sprague B. L., C. G. Pearson, P. S. Maddox, K. S. Bloom, E. D. Salmon, D. J. Odde. Mechanisms of microtubule-based kinetochore positioning in the yeast metaphase spindle. Biophys. J. 84(6):3529–3546, 2003
Stewart R. C., K. Jahreis, J. S. Parkinson. Rapid phosphotransfer to CheY from a CheA protein lacking the CheY-binding domain. Biochemistry 39(43):13157–13165, 2000
Swillens S., M. Paiva, J. E. Dumont. Consequences of the intracellular distribution of cyclic 3’,5’-nucleotides phosphodiesterases. FEBS Lett. 49(1):92–95, 1974
Tostevin F., P. R. ten Wolde, M. Howard. Fundamental limits to position determination by concentration gradients. PLoS Comput. Biol. 3(4):e78, 2007
Vaknin A., H. C. Berg. Single-cell FRET imaging of phosphatase activity in the Escherichia coli chemotaxis system. Proc. Natl. Acad. Sci. USA 101(49):17072–17077, 2004
Wollman R., E. N. Cytrynbaum, J. T. Jones, T. Meyer, J. M. Scholey, A. Mogilner. Efficient chromosome capture requires a bias in the ‘search-and-capture’ process during mitotic-spindle assembly. Curr. Biol. 15(9):828–832, 2005
Zhao R., E. J. Collins, R. B. Bourret, R. E. Silversmith. Structure and catalytic mechanism of the E. coli chemotaxis phosphatase CheZ. Nat. Struct. Biol. 9(8):570–575, 2002
Acknowledgments
The authors acknowledge funding from National Science Foundation Career Award (BES 9984955), NIH-National Institute of General Medical Sciences (GM71522), McKnight Land-Grant Professorship to DJO, Royal Society University Research Fellowship to KL, and from NIH-NIGMS (GM64713) to Dennis Bray. We thank Dennis Bray for helpful discussions, and him and Matthew D. Levin for insightful comments on the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lipkow, K., Odde, D.J. Model for Protein Concentration Gradients in the Cytoplasm. Cel. Mol. Bioeng. 1, 84–92 (2008). https://doi.org/10.1007/s12195-008-0008-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12195-008-0008-8