@article {3936, title = {Where to start and when to stop.}, journal = {Nature Structural \& Molecular Biology}, volume = {13}, year = {2006}, month = {2006 Aug}, pages = {668-70}, abstract = {

The activity of a handful of transcription factors, such as mammalian NF-B, Drosophila melanogaster Cubitus interruptus and yeast Spt23 and Mga2, are regulated through partial protein degradation by the proteasome. New data now show that the proteasome activates membrane-bound Spt23 and Mga2 by initiating their proteolysis at an internal site and then degrading the proteins bidirectionally toward both ends of the polypeptide chain, modifying our ideas on how the proteasome degrades targeted substrates.

}, keywords = {Animals, DNA-Binding Proteins, Drosophila Proteins, Membrane Proteins, NF-kappa B, Oncogene Proteins, Proteasome Endopeptidase Complex, Protein Structure, Saccharomyces cerevisiae Proteins, Tertiary, Trans-Activators, Transcription Factors}, issn = {1545-9993}, doi = {10.1038/nsmb0806-668}, author = {Tian, Lin and Matouschek, Andreas} } @article {3937, title = {A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-kappaB.}, journal = {Nature Structural \& Molecular Biology}, volume = {12}, year = {2005}, month = {2005 Dec}, pages = {1045-53}, abstract = {

The proteasome degrades some proteins, such as transcription factors Cubitus interruptus (Ci) and NF-kappaB, to generate biologically active protein fragments. Here we have identified and characterized the signals in the substrate proteins that cause this processing. The minimum signal consists of a simple sequence preceding a tightly folded domain in the direction of proteasome movement. The strength of the processing signal depends primarily on the complexity of the simple sequence rather than on amino acid identity, the resistance of the folded domain to unraveling by the proteasome and the spacing between the simple sequence and folded domain. We show that two unrelated transcription factors, Ci and NF-kappaB, use this mechanism to undergo partial degradation by the proteasome in vivo. These findings suggest that the mechanism is conserved evolutionarily and that processing signals may be widespread in regulatory proteins.

}, keywords = {Amino Acid Sequence, Animals, Cells, Cultured, DNA-Binding Proteins, Drosophila Proteins, Humans, NF-kappa B p50 Subunit, Proteasome Endopeptidase Complex, Protein Folding, Transcription Factors}, issn = {1545-9993}, doi = {10.1038/nsmb1018}, author = {Tian, Lin and Holmgren, Robert A and Matouschek, Andreas} } @article {3938, title = {An unstructured initiation site is required for efficient proteasome-mediated degradation.}, journal = {Nature Structural \& Molecular Biology}, volume = {11}, year = {2004}, month = {2004 Sep}, pages = {830-7}, abstract = {

The proteasome is the main ATP-dependent protease in eukaryotic cells and controls the concentration of many regulatory proteins in the cytosol and nucleus. Proteins are targeted to the proteasome by the covalent attachment of polyubiquitin chains. The ubiquitin modification serves as the proteasome recognition element but by itself is not sufficient for efficient degradation of folded proteins. We report that proteolysis of tightly folded proteins is accelerated greatly when an unstructured region is attached to the substrate. The unstructured region serves as the initiation site for degradation and is hydrolyzed first, after which the rest of the protein is digested sequentially. These results identify the initiation site as a novel component of the targeting signal, which is required to engage the proteasome unfolding machinery efficiently. The proteasome degrades a substrate by first binding to its ubiquitin modification and then initiating unfolding at an unstructured region.

}, keywords = {Adenosine Triphosphate, Animals, Bacillus, Binding Sites, Biological, Catalysis, Cell Nucleus, Cysteine Endopeptidases, Cytosol, Electrophoresis, Endopeptidases, Escherichia coli, Genetic, Hydrolysis, Models, Multienzyme Complexes, Polyacrylamide Gel, Promoter Regions, Proteasome Endopeptidase Complex, Protein Binding, Protein Folding, Protein Structure, Rabbits, Temperature, Tertiary, Time Factors, Ubiquitin}, issn = {1545-9993}, doi = {10.1038/nsmb814}, author = {Prakash, Sumit and Tian, Lin and Ratliff, Kevin S and Lehotzky, Rebecca E and Matouschek, Andreas} }