Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha 2-Macroglobulin (alpha 2M), a major plasma component in all vertebrates, is proposed to function as a broad spectrum protease inhibitor. The alpha 2M-proteinase complex (activated alpha 2M; alpha 2M*) is removed rapidly by receptor-mediated endocytosis in the liver. Here we demonstrate by Western blotting that alpha 2M is also present in the yolk of chicken oocytes. Plasma levels of alpha 2M are increased by estrogen, and yolk alpha 2M is partially proteolyzed, consistent with the action of cathepsin D on endocytosed alpha 2M. Two known estrogen-induced ligands of the oocyte-specific 95-kDa very low density lipoprotein/vitellogenin receptor (OVR) are also fragmented by yolk cathepsin D (Retzek, H., Steyrer, E., Sanders, E. J., Nimpf, J., and Schneider, W. J. (1992) DNA Cell Biol. 11, 661-672). Since these findings suggested a common uptake mechanism for lipoproteins and alpha 2M by oocytes, we investigated whether OVR, a member of the low density lipoprotein receptor family, functions in the metabolism of alpha 2M. Ligand blotting of oocyte membrane extracts with chicken alpha 2M* revealed that it binds to OVR. Surprisingly, the oocyte receptor also recognizes native alpha 2M, in sharp contrast to the hepatic receptor, which only binds alpha 2M*. Receptor interaction of both forms requires Ca2+; however, competition experiments suggest that alpha 2M and alpha 2M* interact with slightly different, or overlapping, sites on the receptor. Colocalization of alpha 2M and OVR in coated vesicles isolated from growing oocytes, and internalization and degradation of methylamine-activated alpha 2M by COS-7 cells transfected with OVR, strongly suggest that alpha 2M is transported into growing oocytes via OVR. We propose that this multifunctional receptor mediates pathways at the metabolic crossroads of lipoproteins and protease inhibitor complexes.
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PMID:The chicken oocyte receptor for lipoprotein deposition recognizes alpha 2-macroglobulin. 753 64

During the rapid final stage of growth, chicken oocytes take up massive amounts of plasma components and convert them to yolk. The oocyte expresses a receptor that binds both major yolk lipoprotein precursors, vitellogenin (VTG) and very low density lipoprotein (VLDL). In the present study, in vivo transport tracing methodology, isolation of coated vesicles, ligand- and immuno-blotting, and ultrastructural immunocytochemistry were used for the analysis of receptor-mediated yolk formation. The VTG/VLDL receptor was identified in coated profiles in the oocyte periphery, in isolated coated vesicles, and within vesicular compartments both outside and inside membrane-bounded yolk storage organelles (yolk spheres). VLDL particles colocalized with the receptor, as demonstrated by ultrastructural visualization of VLDL-gold following intravenous administration, as well as by immunocytochemical analysis with antibodies to VLDL. Lipoprotein particles were shown to reach the oocyte surface by passage across the basement membrane, which possibly plays an active and selective role in yolk precursor accessibility to the oocyte surface, and through gaps between the follicular granulosa cells. Following delivery of ligands from the plasma membrane into yolk spheres, proteolytic processing of VTG and VLDL by cathepsin D appears to correlate with segregation of receptors and ligands which enter disparate sub-compartments within the yolk spheres. In small, quiescent oocytes, the VTG/VLDL receptor was localized to the central portion of the cell. At onset of the rapid growth phase, it appears that this pre-existing pool of receptors redistributes to the peripheral region, thereby initiating yolk formation. Such a redistribution mechanism would obliterate the need for de novo synthesis of receptors when the oocyte's energy expenditure is to be utilized for plasma membrane synthesis, establishment and maintenance of intracellular topography and yolk formation, and preparation for ovulation.
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PMID:Chicken oocyte growth: receptor-mediated yolk deposition. 839 85