Many physiological processes in cell membranes require lateral diffusion: transport by mobile redox carriers ill mitochondria and chloroplasts, diffusion-coupled activation of G-protein by rhodopsin in rod outer segments, aggregation of mobile receptors for hormones and antibodies. Lateral diffusion is hindered by high concentrations of mobile species, or by the presence of immobile species such as gel-phase lipid domains or immobilized proteins. In this project, the effect of obstacles on diffusion and diffusion-mediated reactions will be analyzed by means of percolation theory and Monte Carlo calculations. The use of lateral diffusion measurements as a probe of submicroscopic domain structure in cell membranes will be modeled, including the effect of lipid domains on diffusion, and measurements of motion of individual particles on the cell surface at nanometer resolution. In many types of cells, the restriction of lateral diffusion of plasma membrane proteins is essential to differentiation. One means of accomplishing this is the membrane skeleton. The spectrin network attached to the erythrocyte plasma membrane is the best-known example, but similar networks are found in other cells, such as epithelial and nerve cells. The membrane skeleton obstructs lateral diffusion and provides mechanical reinforcement to the plasma membrane. This project will continue the development of a unified model of these effects, showing how the integrity of the network affects the diffusion coefficient of membrane proteins, and the elasticity and mechanical stability of the membrane skeleton. The emphasis will be on a model of the breakdown of the membrane skeleton under mechanical stress, to find the probability that a defective membrane skeleton will break down under a given stress, and to characterize gaps in the network where membrane may be lost by vesiculation. The breakdown model will be extended to include the effects of a toughening mechanism and variation in protein- protein binding constants. The results will show the effects of missing, defective, or oxidized spectrin, as in hereditary hemolytic anemia, sickle cell anemia, and stored blood. The model will be further extended to three dimensions to examine the consequences of damage to the cytoskeleton in a wide variety of disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM038133-06A1
Application #
3294206
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1988-02-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Saxton, Michael J (2014) Wanted: scalable tracers for diffusion measurements. J Phys Chem B 118:12805-17
Saxton, Michael J (2012) Wanted: a positive control for anomalous subdiffusion. Biophys J 103:2411-22
Saxton, Michael J (2010) Two-dimensional continuum percolation threshold for diffusing particles of nonzero radius. Biophys J 99:1490-9
Saxton, Michael J (2008) A biological interpretation of transient anomalous subdiffusion. II. Reaction kinetics. Biophys J 94:760-71
Saxton, Michael J (2007) A biological interpretation of transient anomalous subdiffusion. I. Qualitative model. Biophys J 92:1178-91
Saxton, Michael J (2007) Modeling 2D and 3D diffusion. Methods Mol Biol 400:295-321
Deverall, M A; Gindl, E; Sinner, E-K et al. (2005) Membrane lateral mobility obstructed by polymer-tethered lipids studied at the single molecule level. Biophys J 88:1875-86
Ng, Yuen-Keng; Lu, Xinghua; Gulacsi, Alexandra et al. (2003) Unexpected mobility variation among individual secretory vesicles produces an apparent refractory neuropeptide pool. Biophys J 84:4127-34
Saxton, M J (2001) Anomalous subdiffusion in fluorescence photobleaching recovery: a Monte Carlo study. Biophys J 81:2226-40
Saxton, M J (1997) Single-particle tracking: the distribution of diffusion coefficients. Biophys J 72:1744-53

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