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Death and Destruction

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But this correlation leaves unanswered the most important questions: is the aggregation a cause or an effect of the disease, and how might aggregates exert a toxic gain of function to cause disease? Now Neil Bence, Ron Kopito and colleagues from Stanford University (Stanford, CA) have found that protein aggregation impairs the function of the ubiquitin–proteasome system (UPS)... These structures may sequester or jam UPS components... The resulting reduction in UPS function would increase accumulation of unfolded proteins, initiating a positive-feedback loop and a rapid decline in cell viability. ▪ Further reading: Adenoviruses have co-opted one of their important structural proteins to inhibit apoptosis, according to recent results... Felipe Andrade, Antony Rosen (both at the Johns Hopkins University School of Medicine, Baltimore, MD) and colleagues found that adenovirus L4-100K protein is a specific inhibitor of granzyme B (GrB), an apoptosis-inducing protease produced by cytotoxic T and natural killer cells in response to viral infection... As 100K is an important structural protein for the virus, it is present at significant molar excess over GrB... By this time the adenovirus will have replicated and departed from the cell. ▪ Further reading: In the final talk at the conference, Matthew Bogyo (University of California, San Francisco) described an exciting approach that can be used both to profile the activity of entire classes of proteases, and to identify specific inhibitors of individual proteases... Bogyo's starting point is a natural product, E-64, that binds to and covalently modifies the active site of cysteine proteases... Thus columns with only one or a few red spots identify specific inhibitors... Bogyo then tests whether these specific inhibitors have phenotypic effects on whole cells... After isolating specific inhibitors of the proteases, Bogyo will test which proteases are necessary for different parts of the Plasmodium infection cycle. ▪ Further reading: An inhibitor of protein-destruction machinery may explain the delay between cyclin synthesis and degradation... Addition of substrates favored the open conformation, as long as the relevant active site (trypsin-like, chymotrypsin-like, or caspase-like) was not mutated... She now reports that a permanently open gate (resulting from the removal of the protein domain that normally forms the gate) increases the efficiency of each of the proteolytic activities, when the activities are measured individually... But coordination between the activities appears to be lost... Gaczynska has used individual site mutants and the addition of different substrates to derive a pattern of allosteric effects between the three types of sites, and she finds that this allosterism is disrupted when the gate is missing.

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Injection of Emi1 into frog cells (right) blocks mitosis.Reimann/Cell Press
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uro4: Injection of Emi1 into frog cells (right) blocks mitosis.Reimann/Cell Press


Death and Destruction
Injection of Emi1 into frog cells (right) blocks mitosis.Reimann/Cell Press
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Related In: Results  -  Collection

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uro4: Injection of Emi1 into frog cells (right) blocks mitosis.Reimann/Cell Press

View Article: PubMed Central

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

But this correlation leaves unanswered the most important questions: is the aggregation a cause or an effect of the disease, and how might aggregates exert a toxic gain of function to cause disease? Now Neil Bence, Ron Kopito and colleagues from Stanford University (Stanford, CA) have found that protein aggregation impairs the function of the ubiquitin–proteasome system (UPS)... These structures may sequester or jam UPS components... The resulting reduction in UPS function would increase accumulation of unfolded proteins, initiating a positive-feedback loop and a rapid decline in cell viability. ▪ Further reading: Adenoviruses have co-opted one of their important structural proteins to inhibit apoptosis, according to recent results... Felipe Andrade, Antony Rosen (both at the Johns Hopkins University School of Medicine, Baltimore, MD) and colleagues found that adenovirus L4-100K protein is a specific inhibitor of granzyme B (GrB), an apoptosis-inducing protease produced by cytotoxic T and natural killer cells in response to viral infection... As 100K is an important structural protein for the virus, it is present at significant molar excess over GrB... By this time the adenovirus will have replicated and departed from the cell. ▪ Further reading: In the final talk at the conference, Matthew Bogyo (University of California, San Francisco) described an exciting approach that can be used both to profile the activity of entire classes of proteases, and to identify specific inhibitors of individual proteases... Bogyo's starting point is a natural product, E-64, that binds to and covalently modifies the active site of cysteine proteases... Thus columns with only one or a few red spots identify specific inhibitors... Bogyo then tests whether these specific inhibitors have phenotypic effects on whole cells... After isolating specific inhibitors of the proteases, Bogyo will test which proteases are necessary for different parts of the Plasmodium infection cycle. ▪ Further reading: An inhibitor of protein-destruction machinery may explain the delay between cyclin synthesis and degradation... Addition of substrates favored the open conformation, as long as the relevant active site (trypsin-like, chymotrypsin-like, or caspase-like) was not mutated... She now reports that a permanently open gate (resulting from the removal of the protein domain that normally forms the gate) increases the efficiency of each of the proteolytic activities, when the activities are measured individually... But coordination between the activities appears to be lost... Gaczynska has used individual site mutants and the addition of different substrates to derive a pattern of allosteric effects between the three types of sites, and she finds that this allosterism is disrupted when the gate is missing.

No MeSH data available.