Abstract
Although the process of endocytosis of the low density lipoprotein (LDL) macromolecule and its receptor have been the subject of intense experimental research and modeling, there are still conflicting hypotheses and even conflicting data regarding the way receptors are transported to coated pits, the manner by which receptors are inserted before they aggregate in coated pits, and the display of receptors on the cell surface. At first it was considered that LDL receptors in human fibroblasts are inserted at random locations and then transported by diffusion toward coated pits. But experiments have not ruled out the possibility that the true rate of accumulation of LDL receptors in coated pits might be faster than predicted on the basis of pure diffusion and uniform reinsertion over the entire cell surface. It has been claimed that recycled LDL receptors are inserted preferentially in regions where coated pits form, with display occurring predominantly as groups of loosely associated units. Another mechanism that has been proposed by experimental cell biologists which might affect the accumulation of receptors in coated pits is a retrograde membrane flow. This is essentially linked to a polarized receptor insertion mode and also to the capping phenomenon, characterized by the formation of large patches of proteins that passively flow away from the regions of membrane exocytosis. In this contribution we calculate the mean travel time of LDL receptors to coated pits as determined by the ratio of flow strength to diffusion-coefficient, as well as by polarized-receptor insertion. We also project the resulting display of unbound receptors on the cell membrane. We found forms of polarized insertion that could potentially reduce the mean capture time of LDL receptors by coated pits which is controlled by diffusion and uniform insertion. Our results show that, in spite of its efficiency as a possible device for enhancement of the rate of receptor trapping, polarized insertion nevertheless fails to induce the formation of steady-state clusters of receptor on the cell membrane. Moreover, for appropriate values of the flow strength-diffusion ratio, the predicted steady-state distribution of receptors on the surface was found to be consistent with the phenomenon of capping.
Highlights
Endocytosis generally refers to the process by which substances are internalized through the cell membrane
One of the questions addressed in these models was whether or not the random insertion of low density lipoproteins (LDL) receptors into the plasma membrane, followed by pure diffusion and using the measured diffusion coefficient for LDL receptors, could give a rapid enough aggregation of receptors in coated pits to account for the observed rate of removal of LDL from the cell surface
Since an experimentally determined lower bound for the forward rate constant kdu + is (2.3 × 10− 10 ± 1.6) × 10− 10 cm2/s and the value obtained from their model is 1.9 × 10− 10 cm2/s, the answer to that question is that the hypothesis of random insertion and pure diffusion of LDL receptors to coated pits is consistent with experimental observations but just barely
Summary
Endocytosis generally refers to the process by which substances are internalized through the cell membrane. Receptor-mediated endocytosis (RME) is a highly specialized kind of endocytosis in which large protein molecules called receptors project from the cell membrane and couple selectively to ligands such as low density lipoproteins (LDL) [1]. Coated pits and their associated receptors have been studied most extensively in cells grown in culture, and the LDL receptor is the one on which a majority of experimental research has been conducted. The ligand-receptor complexes aggregate in specialized cell-membrane formations called coated pits [2,3,4,5] When these close, they form vesicles which transport the ligand-receptor complexes to the interior of the cell. Experimental results reveal that RME occurs in virtually all eukaryotic cells except the mature erythrocyte [6] and that it provides an entrance mechanism for cell nutrients such as low density lipoproteins (LDL) [7], hormones and growth factors [8], serum transport proteins and antibodies [9], as well as toxins and lectins [10] and even viruses [11]
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