ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein
| Autor: | Stefan F. Lichtenthaler, Qing-Xiang Amy Sang, Taheera Ferdous, Robert M. Petrovich, Bart De Strooper, Marcia L. Moss, Ina Tesseur, Gary Powell, Colin Dingwall, Jörg W. Bartsch, Bin Qi, Douglas A. Lauffenburger, Julia Li Zhong, Uwe Schlomann, Linda G. Griffith, Miles A. Miller, Mara Taverna, Lori L. Edwards, Pei Zhou |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Miller, Miles Aaron, Griffith, Linda G., Lauffenburger, Douglas A. |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
chemistry [ADAM Proteins]
ADAM10 protein human ADAM10 Protein Array Analysis ADAM9 protein human Biochemistry metabolism [Cell Membrane] antagonists & inhibitors [Membrane Proteins] ADAM10 Protein Amyloid beta-Protein Precursor Epidermal growth factor Cell Line Tumor metabolism [Amyloid beta-Protein Precursor] Membrane activity Amyloid precursor protein Humans chemistry [Membrane Proteins] Protease Inhibitors Molecular Biology enzymology [Cell Membrane] biology Cell Membrane P3 peptide Membrane Proteins Cell Biology ADAM Proteins metabolism [Amyloid Precursor Protein Secretases] Peptide Fragments Protein Structure Tertiary metabolism [ADAM Proteins] ddc:540 pharmacology [Peptide Fragments] Enzymology Biocatalysis biology.protein drug effects [Cell Membrane] drug effects [Biocatalysis] Amyloid Precursor Protein Secretases pharmacology [Protease Inhibitors] ADAM9 Amyloid precursor protein secretase metabolism [Membrane Proteins] antagonists & inhibitors [ADAM Proteins] |
| Zdroj: | American Society for Biochemistry and Molecular Biology The journal of biological chemistry 286(47), 40443-40451 (2011). doi:10.1074/jbc.M111.280495 |
| DOI: | 10.1074/jbc.M111.280495 |
| Popis: | Prodomains of A disintegrin and metalloproteinase (ADAM) metallopeptidases can act as highly specific intra- and intermolecular inhibitors of ADAM catalytic activity. The mouse ADAM9 prodomain (proA9; amino acids 24–204), expressed and characterized from Escherichia coli, is a competitive inhibitor of human ADAM9 catalytic/disintegrin domain with an overall inhibition constant of 280 ± 34 nm and high specificity toward ADAM9. In SY5Y neuroblastoma cells overexpressing amyloid precursor protein, proA9 treatment reduces the amount of endogenous ADAM10 enzyme in the medium while increasing membrane-bound ADAM10, as shown both by Western and activity assays with selective fluorescent peptide substrates using proteolytic activity matrix analysis. An increase in membrane-bound ADAM10 generates higher levels of soluble amyloid precursor protein α in the medium, whereas soluble amyloid precursor protein β levels are decreased, demonstrating that inhibition of ADAM9 increases α-secretase activity on the cell membrane. Quantification of physiological ADAM10 substrates by a proteomic approach revealed that substrates, such as epidermal growth factor (EGF), HER2, osteoactivin, and CD40-ligand, are increased in the medium of BT474 breast tumor cells that were incubated with proA9, demonstrating that the regulation of ADAM10 by ADAM9 applies for many ADAM10 substrates. Taken together, our results demonstrate that ADAM10 activity is regulated by inhibition of ADAM9, and this regulation may be used to control shedding of amyloid precursor protein by enhancing α-secretase activity, a key regulatory step in the etiology of Alzheimer disease. National Institutes of Health (U.S.) (Grant R01EB010246) National Institutes of Health (U.S.) (Grant R01GM081336) Heptagon Fund (London, England) Cancer Research UK Whitehead Foundation Duke University. School of Medicine (Bridge Funding Program) Germany. Bundesministerium für Bildung und Forschung China (National Fellowship from the Chinese Scholarship Council) Florida State University |
| Databáze: | OpenAIRE |
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