Marion Schmidt
Albert Einstein College of Medicine, Biochemistry, Department Member
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Eukaryotic 20S proteasomes harbor a remarkably complex architecture and unique proteolytic properties. Its catalytic mechanism places this enzyme in a new kind of protease family. The recently solved crystal structure of the yeast 20S... more
Eukaryotic 20S proteasomes harbor a remarkably complex architecture and unique proteolytic properties. Its catalytic mechanism places this enzyme in a new kind of protease family. The recently solved crystal structure of the yeast 20S complex, along with elucidation of the maturation pathway of human proteasomes, has allowed insight into structure/function relationships. Although not all of the unusual enzymatic properties such as broad substrate specificity, predominant generation of peptides with a specific size, or susceptibility to activating complexes can be explained in detail, knowledge of the structure provides important hints for an explanation of underlying mechanisms. Except for ribosome biogenesis, the complexity of eukaryotic proteasome maturation is without precedence. It is a slow process that involves a series of precisely ordered events. Proteasome structure formation is characterized by an initial cooperative formation of an alpha ring matrix, providing docking sites for a defined subset of beta subunits. Subsequent structural rearrangement allows the residual subunits to bind, followed by dimerization of two half-proteasomes. The prosequences of beta subunits exert specific functions during this process and are removed by cis- and trans-autocatalysis, most likely in the completely assembled proteasome cylinder.
Research Interests: Physiology, Catalytic Mechanism, Saccharomyces cerevisiae, Crystal structure, Humans, and 10 moreAnimals, Medical Physiology, Enzyme, Protein Secondary Structure Prediction, Substrate Specificity, Multienzyme complexes, Cysteine endopeptidases, Protein Conformation, Biochemistry and cell biology, and Dimerization
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Eukaryotic 20S proteasomes are complex oligomeric proteins. The maturation process of the 14 different alpha- and beta-subunits has to occur in a highly coordinate manner. In addition beta-subunits are synthesized as proproteins and... more
Eukaryotic 20S proteasomes are complex oligomeric proteins. The maturation process of the 14 different alpha- and beta-subunits has to occur in a highly coordinate manner. In addition beta-subunits are synthesized as proproteins and correct processing has to be guaranteed during complex maturation. The structure formation can be subdivided in different phases. The knowledge of the individual phases is summarized in this publication. As a first step the newly synthesized monomers have to adopt the correct tertiary structure, a process that might be supported in the case of the beta-subunits by the intramolecular chaperone activity postulated for the prosequences. Subsequently the alpha-subunits form ring-like structures thereby providing docking sites for the different beta-subunits. The result most likely is a double ring structure (13S precursor) representing half-proteasomes, which contain immature proproteins. Two 13S precursors associate to form the proteolytically inactive 16S ...
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Eukaryotic 20S proteasomes harbor a remarkably complex architecture and unique proteolytic properties. Its catalytic mechanism places this enzyme in a new kind of protease family. The recently solved crystal structure of the yeast 20S... more
Eukaryotic 20S proteasomes harbor a remarkably complex architecture and unique proteolytic properties. Its catalytic mechanism places this enzyme in a new kind of protease family. The recently solved crystal structure of the yeast 20S complex, along with elucidation of the maturation pathway of human proteasomes, has allowed insight into structure/function relationships. Although not all of the unusual enzymatic properties such as broad substrate specificity, predominant generation of peptides with a specific size, or susceptibility to activating complexes can be explained in detail, knowledge of the structure provides important hints for an explanation of underlying mechanisms. Except for ribosome biogenesis, the complexity of eukaryotic proteasome maturation is without precedence. It is a slow process that involves a series of precisely ordered events. Proteasome structure formation is characterized by an initial cooperative formation of an alpha ring matrix, providing docking sit...
Research Interests: Physiology, Catalytic Mechanism, Saccharomyces cerevisiae, Crystal structure, Humans, and 10 moreAnimals, Medical Physiology, Enzyme, Protein Secondary Structure Prediction, Substrate Specificity, Multienzyme complexes, Cysteine endopeptidases, Protein Conformation, Biochemistry and cell biology, and Dimerization
A total of 114 healthy young adults were immunized with hepatitis A vaccine using different vaccination schedules. Individuals received either a single dose (group 1), two doses given simultaneously (group 2), two doses at days 0 and 14... more
A total of 114 healthy young adults were immunized with hepatitis A vaccine using different vaccination schedules. Individuals received either a single dose (group 1), two doses given simultaneously (group 2), two doses at days 0 and 14 (group 3) or at days 0 and 28 (group 4), or three doses at days 0, 7 and 21 (group 5). Two weeks after a single dose, seroconversion rates between 77 and 85% were achieved (groups 1, 3, 4). All individuals immunized with two doses within two weeks (groups 2, 3, 5) had antibodies to hepatitis A vaccine (anti-HAV positive) by week 3; these participants also showed clearly higher mean anti-HAV values (geometric mean titres, GMTs) at this time than those individuals vaccinated only once. GMTs at week 8 were 560 IU/l in group 5, 236, 339 and 428 IU/l in groups 2-4 and 102 IU/l in group 1. Of participants with anti-HAV at week 8, 82 were again tested 4 months later; all were still seropositive. Ten individuals were tested during the first three weeks at 3-...
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The proteasome, a validated anticancer target, participates in an array of biochemical activities, which range from the proteolysis of defective proteins to antigen presentation. We report the preparation of biochemically and... more
The proteasome, a validated anticancer target, participates in an array of biochemical activities, which range from the proteolysis of defective proteins to antigen presentation. We report the preparation of biochemically and photophysically distinct green, red, and far-red real-time sensors designed to simultaneously monitor the proteasome's chymotrypsin-, trypsin-, and caspase-like activities, respectively. These sensors were employed to assess the effect of simultaneous multiple active site catalysis on the kinetic properties of the individual subunits. Furthermore, we have found that the catalytic signature of the proteasome varies depending on the source, cell type, and disease state. Trypsin-like activity is more pronounced in yeast than in mammals, whereas chymotrypsin-like activity is the only activity detectable in B-cells (unlike other mammalian cells). Furthermore, chymotrypsin-like activity is more prominent in transformed B cells relative to their counterparts from ...
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Nineteen healthy young adults were vaccinated with plasma-derived hepatitis B vaccine at months 0, 1, and 12, and their immune responses were compared to those of a similar group of 20 vaccinees immunized at months 0, 1, and 6. Late... more
Nineteen healthy young adults were vaccinated with plasma-derived hepatitis B vaccine at months 0, 1, and 12, and their immune responses were compared to those of a similar group of 20 vaccinees immunized at months 0, 1, and 6. Late booster injections at 12 months produced nearly fivefold higher geometric mean anti-HBs levels than those of the control group. The higher anti-HBs values may lead to longer persistence of anti-HBs and thus to longer protection against hepatitis B.
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No differences in eventual immune-response rates were found between 325 subjects immunized passively/actively against hepatitis B and a control group of 108 subjects vaccinated only actively. The geometric mean titers of antibodies to... more
No differences in eventual immune-response rates were found between 325 subjects immunized passively/actively against hepatitis B and a control group of 108 subjects vaccinated only actively. The geometric mean titers of antibodies to hepatitis B surface antigen were nearly identical in controls and in a group of 87 individuals immunized passively/actively with the same vaccine lot. Lower geometric mean titers of antibodies to hepatitis B surface antigen were seen in 238 individuals who were vaccinated passively/actively with a different vaccine lot, a difference that may be explained by a somewhat lower immunogenicity in this particular lot. The mean half-life of hepatitis B immunoglobulin was calculated as 24.8 days, and in approximately 90% of vaccines 300,000 mIU of hepatitis B immunoglobulin provided protection until an active immune response had developed.
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The immunogenicity and reactogenicity of different doses of hepatitis A vaccine was studied in healthy adult volunteers. Vaccinees (105) were immunized with 6.25, 12.5 or 25 ng of HAV antigen, each dose administered at 0, 1 and 6 months... more
The immunogenicity and reactogenicity of different doses of hepatitis A vaccine was studied in healthy adult volunteers. Vaccinees (105) were immunized with 6.25, 12.5 or 25 ng of HAV antigen, each dose administered at 0, 1 and 6 months (groups B, C and D); one group (group A) obtained three 6.25 ng doses at 0, 1 and 2 months. After one single dose high seroconversion rates ranging between 63 and 85% were observed in all four groups. All participants had seroconverted after the third dose, irrespective of the antigen content per dose and the vaccination schedule. Geometric mean titers after three doses were 439 IU/l (group A, month 3) and 1492, 963 and 2772 IU/l in groups B, C and D at month 7. One year after the first injection all vaccinees tested still showed antibody levels well above 10 IU/l. The vaccine was very well tolerated. Minor localized symptoms were observed mainly such as slight pain at the injection site. These symptoms were not dose related; no serious side effects occurred.
Research Interests: Immune response, Hepatology, Humans, Female, Male, and 4 moreVaccination, Clinical Sciences, Middle Aged, and Adult
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Research Interests: Kinetics, Cell line, Hepatitis B, Humans, Mice, and 19 moreAnimals, Antigen Processing, The, Proteins, Peripheral blood lymphocyte, HeLa cells, Major histocompatibility complex, Experimental Medicine, Multienzyme complexes, Cysteine endopeptidases, Transfection, Amino Acid Sequence, Hepatitis B virus, Structure activity Relationship, chronic hepatitis B, MHC class I, Low molecular weight, Interferon gamma, and Molecular Sequence Data
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Flexible packaging films for highly sensitive products that are to be protected against moisture and oxygen need high barrier materials. In the food and pharmaceutical packaging industries, barrier films, which contain a single inorganic... more
Flexible packaging films for highly sensitive products that are to be protected against moisture and oxygen need high barrier materials. In the food and pharmaceutical packaging industries, barrier films, which contain a single inorganic layer on top of a polymeric substrate, provide sufficient barrier. For the protection of more sensitive products, such as vacuum insulation panels, organic photovoltaic cells, or
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Automated sample preparation systems must meet the demands of routine diagnostics laboratories with regard to performance characteristics and compatibility with downstream assays.