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Proteomics studies on the basic biology of Alzheimer's, cancer and listeriosis

July 18, 2018

Alzheimer's protease curates neuron surfaces

The brains of people with Alzheimer's disease contain many protein aggregates outside of cells, known as plaques. These are mainly made of the peptide amyloid-beta, which is released from the plasma membrane when the protease BACE1 cleaves its membrane-anchored precursor protein. Because amyloid-beta cannot be produced without BACE1, numerous BACE1 inhibitors have been tested or are in clinical trials as Alzheimer's therapy.

In a recent article in Molecular & Cellular Proteomics, Julia Herber and colleagues at the German Center for Neurodegenerative Diseases described how they used a targeted surface glycoproteomics method to observe the effects of BACE1 inhibition. By labeling glycosylated membrane proteins, the researchers showed that BACE1 inhibition increases the abundance of unprocessed amyloid precursor protein but also increases other BACE1 substrates and even nonsubstrate proteins. This suggests that the inhibitor may exert unanticipated side effects by remodeling neuronal surface proteomes.

DOI: 10.1074/mcp.RA118.000608
http://www.mcponline.org/content/early/2018/04/30/mcp.RA118.000608

Linking cancer's sweet tooth and distaste for fiber

Cancer cells are strange. For energy, they rely on aerobic glycolysis, a relatively inefficient way of getting energy out of glucose, instead of shuttling glycolysis products into the mitochondria to finish breaking them down. Besides this widespread preference of most cancers, known as the Warburg effect, colorectal cancer cells have an extra metabolic quirk called the butyrate paradox. Whereas healthy cells in the colon depend on butyrate, a short-chain fatty acid made by bacteria in the digestive system, for a majority of their energy, cancerous cells are less able to proliferate when butyrate is available.

Researchers at China Pharmaceutical University in Nanjing reported on their studies of the metabolic changes in colorectal cancer cells in a recent paper in Molecular & Cellular Proteomics. The work zeroed in on the cells' distaste for butyrate and preference for glycolysis. Qingran Li and colleagues used a metabolomics screen and found that cancer cells, after treatment with butyrate, tend to activate mitochondrial oxidation and stop using glycolysis products to generate new nucleotides and amino acids. The researchers showed that butyrate pushes this metabolic remodeling by binding to pyruvate kinase isoform M2, or PKM2, and activating it. Active PKM2 generates pyruvate, the starting point of the Krebs cycle. This research adds evidence to the existing hypothesis that turning up PKM2 may suppress tumor growth.

DOI: 10.1074/mcp.RA118.000752
http://www.mcponline.org/content/early/2018/05/08/mcp.RA118.000752

Listeriolyin's pore-forming toxin uses protein modification to get its way

It's a tale nearly as old as genetic information: one set of cells would like to continue its daily business of protein synthesis and replication, while another would like to sabotage those mechanisms for its own gain. When the pathogen Listeria monocytogenes, of foodborne infamy, finagles its way inside epithelial cells in the human intestines, the bacterium deploys the pore-forming toxin Listeriolysin O, or LLO, which interferes with the proteins synthesized by the infected cell. This ultimately results in cell death by creating holes in the cell membranes.

In a paper in Molecular & Cellular Proteomics, researchers at the Pasteur Institute in Paris describe a proteomics analysis of human epithelial cells treated with LLO, in which they found that the toxin acts exclusively by altering host proteins through post-translational modifications involving ubiquitin, rather than affecting transcriptional activity of underlying genes. They also found that a similar toxin, Perfringolysin O, acts through proteome remodeling.

DOI 10.1074/mcp.RA118.000767
http://www.mcponline.org/content/early/2018/05/11/mcp.RA118.000767.abstract
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About Molecular & Cellular Proteomics

Molecular & Cellular Proteomics (MCP) showcases research into proteomes, large-scale sets of proteins from different organisms or biological contexts. The journal publishes work that describes the structural and functional properties of proteins and their expression, particularly with respect to developmental time courses. Emphasis is placed on determining how the presence or absence of proteins affect biological responses, and how the interaction of proteins with their cellular partners influences their functions. For more information about MCP, visit http://www.mcponline.org.

American Society for Biochemistry and Molecular Biology

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