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Internalization of Receptors

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Internalization of Receptors
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Figure 20.32 Proposed arrangement of b ­adrenergic receptor helices in the membrane. Lower portion of the figure is a view from above the plane of the plasma membrane. It is proposed that helices IV, VI, and VII are arranged in the membrane in such a way as to delineate a ligand­binding pocket, with helix VII centrally located. Adapted from Frielle, T., Daniel, K. W., Caron, M. G., and Lefkowitz, R. J. Proc. Natl. Acad. Sci. USA 85:9494, 1988.
The long extended chain from VII may contain phosphorylation sites (serine and threonine residues) of the receptor, which are important in terms of the receptor regulatory process involving receptor desensitization. Phosphorylation of these residues within the cytoplasmic tail of the receptor results in the binding of an inhibitory protein, called b arrestin, which blocks the receptor's ability to activate Gs. Cell exterior peptide loops extend from II to III, IV to V, and VI to VII, but mutational analysis suggests that the external loops do not take part in ligand binding. It appears that ligand binding may occur in a pocket arranged by the location of the membrane­spanning cylinders I–VII, which for the 1 receptor appear to form a ligand pocket, as shown from a top view in Figure 20.32. Recently reported work suggests that transmembrane domain VI may play a role in the stimulation of adenylate cyclase activity. By substitution of a specific cysteine residue in this transmembrane domain, a mutant was generated that displays normal ligand­binding properties but a decreased ability to stimulate the cyclase.
20.11— Internalization of Receptors
Up to now we have described receptor systems that transduce signals through other membrane proteins, such as G­proteins, which move about in the fluid
Figure 20.33 Diagrammatic summary of the morphological pathway of endocytosis in cells. The morphological elements of the pathway of endocytosis are not drawn to scale. The ligands shown as examples are EGF, transferrin, and ­macroglobulin. EGF is 2
an example of a receptor system in which both ligand and receptor are delivered to lysosomes; transferrin is shown as an example of a system in which both the ligand and receptor recycle to the surface; ­macroglobulin is shown as an example of a 2
system in which the ligand is delivered to lysosomes but the receptor recycles efficiently back to the cell surface via the Golgi apparatus. Adapted from Pastan, I., and Willingham, M. C. (Eds.). Endocytosis. New York: Plenum Press, 1985, p. 3.
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cell membrane. However, many types of cell membrane hormone–receptor complexes are internalized, that is, moved from the cell membrane to the cell interior by a process called endocytosis. This would represent the opposite of exocytosis in which components within the cell are moved to the cell exterior. The process of endocytosis as presented in Figure 20.33 involves the polypeptide–receptor complex bound in coated pits, which are indentations in the plasma membrane that invaginate into the cytosol and pinch off from the membrane to form coated vesicles. The vesicles shed their coats, fuse with each other, and form vesicles called receptosomes. The receptors and ligands on the inside of these receptosomes can have different fates. Receptors can be recycled to the cell surface following fusion with the Golgi apparatus. Alternatively, the vesicles can fuse with lysosomes for degradation of both the receptor and hormone. In addition, some hormone–receptor complexes are dissociated in the lysosome and only the hormone is degraded, while the receptor is returned intact to the membrane. In some systems, the receptor may also be concentrated in coated pits in the absence of exogenous ligand and cycle in and out of the cell in a constitutive, nonligand­dependent manner.
Clathrin Forms a Lattice Structure to Direct Internalization of Hormone–Receptor Complexes from the Plasma Membrane
The major protein component of the coated vesicle is clathrin, a nonglycosylated protein of mol wt 180,000 whose amino acid sequence is highly conserved. The coated vesicle contains 70% clathrin, 5% polypeptides of about 35 kDa, and 25% polypeptides of 50–100 kDa. Aspects of the structure of a coated vesicle are shown in Figure 20.34. Coated vesicles have a lattice­like surface
Figure 20.34 Structure and assembly of a coated vesicle. (a) A typical coated vesicle contains a membrane vesicle about 40 nm in diameter surrounded by a fibrous network of 12 pentagons and 8 hexagons. The fibrous coat is constructed of 36 clathrin triskelions. One clathrin triskelion is centered on each of the 36 vertices of the coat. Coated vesicles having other sizes and shapes are believed to be constructed similarly: each vesicle contains 12 pentagons but a variable number of hexagons. (b) Detail of a clathrin triskelion. Each of three clathrin heavy chains is bent into a proximal arm and a distal arm. A clathrin light chain is attached to each heavy chain, most likely near the center. (c) An intermediate in the assembly of a coated vesicle, containing 10 of the final 36 triskelions, illustrates the packing of the clathrin triskelions. Each of the 54 edges of a coated vesicle is constructed of two proximal and two distal arms intertwined. The 36 triskelions contain 36 × 3 = 108 proximal and 108 distal arms, and the coated vesicle has precisely 54 edges. See Crowther, R. A., and Pearse, B. M. F. J. Cell Biol. 91:790, 1981. Redrawn from Nathk, I. S., Heuser, J., Lupas, A., Stock, J., Turck, C. W., and Brodsky, E. M. Cell 68:899, 1992. Redrawn from Darnell, J., Lodish, H., and Baltimore, D. Molecular Cell Biology. New York: Scientific American Books, 1986, p. 647.
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