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)

The crystal structures of complexes of the aspartic proteinases, human and mouse renins, yeast proteinase A and cathepsin D, with peptide analogue inhibitors are compared. Differences occur in the relative positions of the domain comprising residues 190-302 (pepsin numbering) compared to the remaining structure and in the nature and position of the irregular regions joining the beta-strands and alpha-helices. The first three of the five residues of the oligosaccharide structures attached to Asn 67 of yeast proteinase and cathepsin D cover the same region of the protein surface. All enzymes have an unusual, proline-rich region (292-297) which acts as a second flap (in addition to that involving residues 72-81). This covers the active site cleft, but can be very close to the substrate/inhibitor at P3' and P4' only in the renins.
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PMID:Comparisons of the three-dimensional structures, specificities and glycosylation of renins, yeast proteinase A and cathepsin D. 854 Mar 15

The process of apoptosis (programmed cell death) has become the subject of intensive and extensive research over the past few years. Various approaches are being used to identify and study genes which function as positive mediators of apoptosis. Here, we address a novel approach of gene cloning aimed at isolating intracellular death promoting genes by utilizing a functional screen. This method, called TKO, was based on transfection of cells with an anti-sense cDNA library, followed by the selection of transfectants which survived in the continuous presence of a killing cytokine-interferon-gamma. It led to the identification of five novel apoptotic genes and to the finding that a known protease-cathepsin D, is actively recruited to the death process. The five novel apoptotic genes (named DAP genes for: Death Associated Proteins) code for proteins which display a diverse spectrum of biochemical activities. The list comprises a novel type of calcium/calmodulin-regulated kinase which carries ankyrin repeats and a death domain (DAP-kinase), a nucleotide-binding protein (DAP-3), a small proline-rich cytoplasmic protein (DAP-1), and a novel homolog of the eIF4G translation initiation factor (DAP-5). Extensive studies proved that these genes are critical for mediating cell death initiated by interferon-gamma, and in some of the tested cases also cell death induced by Fas/APO-1, TNF-alpha, and a detachment from extracellular matrix. Moreover, one of these genes, DAP-kinase, was recently found to display strong tumor suppressive activities, coupling the control of apoptosis to metastasis. The advantage of functional approaches of gene cloning is that they select the relevant rate limiting genes along the death pathways in a complete unbiased manner. As a consequence, novel targets and unpredicted mechanisms emerged. A few examples illustrating this important point will be discussed. One relates to the calcium/calmodulin-dependent DAP-kinase, which is localized to the actin microfilaments. It was found that the correct localization of DAP-kinase to the microfilament network was critical for the execution of the apoptotic process, and more specifically for the disruption of the stress fibers--a typical hallmark of apoptosis. Another important breakthrough step in our understanding of apoptotic processes relates to the identification and analysis of the DAP-5 gene. The structure/ function features of this novel translation regulator resemble the proteolytically cleaved eIF4G which appears in cells upon infection with some RNA viruses and which directs cap-independent translation. Thus, the rescue of DAP-5 highlighted the importance of regulation of protein translation in certain apoptotic systems. Finally, the isolation of cathespin D by our method suggests that lysosomal proteases are recruited during apoptosis, in addition to the well known caspase family of proteases, and that a unique pattern of regulation affecting the processing of this protease takes place. The major challenge now is to analyse how these diverse DAP gene activities constitute biochemical pathway(s) leading to programmed cell death, and what is their functional position with respect to other known positive mediators and suppressors of apoptosis such as the Bcl2 and caspase family members.
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PMID:Death associated proteins (DAPs): from gene identification to the analysis of their apoptotic and tumor suppressive functions. 991 95

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell-cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase- and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.
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PMID:The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse. 1659 35