C the experiments in figure 1917 and the absence of

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C. The experiments in Figure 19–17 (and the absence of an effect with meta- bolic poisons) indicate that a 5 b 1 integrin can exist in low-affinity and high- affinity states. Apparently, the anti- b 1 antibody, by binding to a specific site on the b 1 chain, induces a conformational change in the a 5 b 1 integrin that flips it into its high-affinity state, or traps it there. Such conformational changes would be expected to occur only upon binding of antibodies to rare, special sites (which correlates with the rarity of monoclonal antibodies that have the properties of this particular anti- b 1 antibody). Low- and high-affin- ity states appear to be common for integrins. In many cases, the affinity can be altered by events occurring within the cell. Reference: Faull RJ, Kovach NL, Harlan JM & Ginsberg MH (1993) Affinity modulation of integrin a 5 b 1 : regulation of the functional response by solu- ble fibronectin. J. Cell Biol. 121, 155–162. 19–67 A. The a IIb b 3 integrin, like the a 5 b 1 integrin described in Problem 19–66, can exist in two conformations: one with very low affinity for fibrinogen and the other with very high affinity. Evidently, the cytoplasmic domain of the a IIb chain controls the affinity of this integrin. In CHO cells, the cytoplasmic domain holds the integrin in its low-affinity conformation. Truncation of the cytoplasmic domain allows the integrin to flip into its high-affinity con- formation. B. If the affinity of the a IIb b 3 integrin is regulated by the cytoplasmic domain of a IIb, as suggested by the answer to part A, then the factors that stimulate clotting presumably initiate a cell-signaling pathway that alters the affinity of the integrin via effects on the cytoplasmic domain of a IIb. Thrombin has no effect on CHO cells that display a IIb b 3 integrin on their surface because the thrombin receptor or a portion of the thrombin-induced signaling path- way is missing in CHO cells. INTEGRINS AND CELL MATRIX ADHESION A449
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C. Individuals who carry one gene for a IIb with a mutation like the one described in this problem would be expected to have blood-clotting prob- lems. Although half the a IIb b 3 integrin in their platelets would be normal, half would be expected to have a high affinity for fibrinogen and cause platelet aggregation and blood clotting in the absence of thrombin stimula- tion. Thus, such a mutation would be expected to be dominant and cause serious problems, even in individuals who are heterozygous for the muta- tion. Reference: O’Toole TE, Mandelman D, Forsyth J, Shattil SJ, Plow EF & Gins- berg MH (1991) Modulation of the affinity of integrin a IIb b 3 (GPIIb-IIIa) by the cytoplasmic domain of a IIb . Science 254, 845–847. THE EXTRACELLULAR MATRIX OF ANIMALS DEFINITIONS 19–68 Collagen 19–69 Extracellular matrix 19–70 Glycosaminoglycan (GAG) 19–71 Fibrillar collagen 19–72 Fibronectin 19–73 Elastin 19–74 Fibroblast TRUE/FALSE 19–75 False. The extracellular matrix plays an active role influencing the develop- ment, migration, proliferation, shape, and metabolism of cells that contact it.
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