常见的第四版 第16章__细胞死亡与细胞衰老.ppt

以线虫为研究材料。线虫属于线形动物，是我们熟知的蛔虫的近亲。线虫长仅１毫米，通体透明，便于用显微镜观测。它的体细胞数目是恒定的，共1090个，其中131个在发育过程中发生细胞“程序性死亡”。 * * The binding of B cell lymphoma 2 (BCL-2) homology 3 domain (BH3)-only proteins to BCL-2-associated X protein (BAX) and BCL-2 antagonist or killer (BAK) leads to extensive conformational changes during their activation. The BH3 domain and hydrophobic cleft are exposed, allowing symmetrical BAX or BAK dimers to form through reciprocal BH3 domain–cleft interactions. During activation, a dimer–dimer interaction surface is also exposed, allowing higher-order oligomers to form. Higher-order oligomers promote mitochondrial outer membrane permeabilization (MOMP) by unclear means, perhaps through forming proteinaceous channels or by destabilizing lipid membranes and forming lipidic pores. IMS, intermembrane space. * 图片来源：http://protein.bio.msu.ru/biokhimiya/contents/v70/fullhtml * 图片来源：/nri/journal/v2/n10/fig_tab/nri911_F1.html a | The initial model, which was developed in the early 1980s when perforin was first purified, emphasized the role of perforin as a lytic molecule. The target cell died because of loss of plasma-membrane homeostasis, with excessive uptake of water and loss of intracellular contents. b | With the realization that granzymes are involved in inducing cell death cooperatively with perforin, and that many cells die by apoptosis, the lytic model was adapted to accommodate the passive diffusion of granzymes into the target-cell cytosol, where they could access key substrates (caspases), leading to apoptotic death. c | The next main findings to be accommodated in the model during the mid to late 1990s were that: granzymes enter target cells by endocytosis independently of perforin, although the target cell remains healthy and granzymes remain harmlessly sequestered in endocytic vesicles in the absence of perforin; small doses of perforin (that cause minimal cell-membrane damage) can synergize with granzymes A and B to induce rapid apoptosis; perfori