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141.
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Abstract: One of the pathological changes of Alzheimer's disease is the deposit of β/A4 protein, which is derived from Alzheimer amyloid precursor protein (APR). In the secretory pathway, APR is cleaved at an internal region of β/A4 protein by a hypothetical enzyme “secretase.” Our previous study showed that the site of cleavage of APR by secretase is determined by the length from the membrane-spanning region. To investigate the role of the transmem- brane region in APR secretion, we constructed the mutations of triplet lysine residues (Lys724-Lys725-Lys726), which are located just in the carboxyl region after the proposed membrane domain. The mutations were as follows: VVK, Val724-Val725-Lys726; LLI, Leu724-Leu725-lle726; and EEE, Glu724-Glu725-Glu726. Wild-type APR and mutant APPs were expressed transiently in COS-1 cells by cDNA trans-fection. The hydrophobic mutant VVK and LLI were processed and secreted in a way similar to that of the wild- type APR, although the rate of secretion was decreased. The acidic mutant EEE was not secreted into medium. Proteinase K treatment and cell surface biotinylation of the COS-1 cells expressing APR revealed that APR was located in the plasma membrane with a short intracellular carboxyl region. However, EEE was completely digested by proteinase K treatment, which suggested that the whole residues of this mutant are located at the outer surface of the cell, including its proposed membrane domain and carboxyl region. This mutant was not cleaved at all by secretase. These findings suggested that the triplet lysine residues of APR after the predicted membrane spanning domain play an important role in the membrane anchorage. In addition, the membrane anchorage was also important for the normal processing by secretase. 相似文献
143.
Myelin Basic Protein Cleaves Cell Adhesion Molecule L1 and Promotes Neuritogenesis and Cell Survival
David Lutz Gabriele Loers Ralf Kleene Iris Oezen Hardeep Kataria Nainesh Katagihallimath Ingke Braren George Harauz Melitta Schachner 《The Journal of biological chemistry》2014,289(19):13503-13518
The cell adhesion molecule L1 is a Lewisx-carrying glycoprotein that plays important roles in the developing and adult nervous system. Here we show that myelin basic protein (MBP) binds to L1 in a Lewisx-dependent manner. Furthermore, we demonstrate that MBP is released by murine cerebellar neurons as a sumoylated dynamin-containing protein upon L1 stimulation and that this MBP cleaves L1 as a serine protease in the L1 extracellular domain at Arg687 yielding a transmembrane fragment that promotes neurite outgrowth and neuronal survival in cell culture. L1-induced neurite outgrowth and neuronal survival are reduced in MBP-deficient cerebellar neurons and in wild-type cerebellar neurons in the presence of an MBP antibody or L1 peptide containing the MBP cleavage site. Genetic ablation of MBP in shiverer mice and mutagenesis of the proteolytically active site in MBP or of the MBP cleavage site within L1 as well as serine protease inhibitors and an L1 peptide containing the MBP cleavage site abolish generation of the L1 fragment. Our findings provide evidence for novel functions of MBP in the nervous system. 相似文献
144.
Heparanase processing by lysosomal/endosomal protein preparation 总被引:6,自引:0,他引:6
Heparanase is an endo-beta-glucuronodase involved in cleavage of heparan sulfate side chains, activity that is strongly implicated in cell dissemination associated with tumor metastasis and inflammation. Heparanase is first synthesized as a latent 65 kDa precursor that is converted into an active enzyme upon proteolytic processing. Previously, we have reported that elevation of the lysosomal pH results in complete inhibition of heparanase processing, suggesting that lysosomal protease(s) and acidic pH conditions are required for heparanase processing. Here, we adopted a cell fractionation approach and provide evidence that incubation of the pro-enzyme with lysosome/endosome, but not with cytoplasmic fractions resulted in processing and activation of the 65 kDa latent heparanase. Moreover, while the water soluble lysosome/endosome fraction exhibited no apparent processing activity, heparanase processing by the water insoluble lysosome/endosome membrane fraction was readily detected and exhibited the expected pH dependency. 相似文献
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147.
Cathepsin S is unique among mammalian cysteine cathepsins in being active and stable at neutral pH. We show that autocatalytic activation of procathepsin S at low pH is a bimolecular process that is considerably accelerated (approximately 20-fold) by glycosaminoglycans and polysaccharides such as dextran sulfate, chondroitin sulfates A and E, and dermatan sulfate through electrostatic interaction with the proenzyme. Procathepsin S is also shown to undergo autoactivation at neutral pH in the presence of dextran sulfate with t1/2 of approximately 20 min at pH 7.5. This novel property of procathepsin S may have implications in pathological conditions associated with the appearance of active cathepsins outside lysosomes. 相似文献
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149.
The time course of tick-borne encephalitis virus cell-free protein synthesis was studied by using either [35S]-methionine or formyl[35S]methionyl-tRNAfMet as substrates, and the [35S]methionine-labelled products were compared by fingerprinting tryptic peptides. An intermediate in the protein processing, the polypeptide doublet p36/33, was characterized and a tentative model for flavivirus structural protein synthesis and processing was proposed. 相似文献
150.