title: Sequence composition of disordered regions fine-tunes protein half-life.
abstract: The proteasome controls the concentrations of most proteins in eukaryotic cells. It recognizes its protein substrates through ubiquitin tags and initiates degradation at disordered regions within the substrate. Here we show that the proteasome has pronounced preferences for the amino acid sequence of the regions at which it initiates degradation. Specifically, proteins in which the initiation regions have biased amino acid compositions show longer half-lives in yeast than proteins with unbiased sequences in the regions. The relationship is also observed on a genomic scale in mouse cells. These preferences affect the degradation rates of proteins in vitro, can explain the unexpected stability of natural proteins in yeast and may affect the accumulation of toxic proteins in disease. We propose that the proteasome's sequence preferences provide a second component to the degradation code and may fine-tune protein half-life in cells.
authors: 1] Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA. [2] Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
authors: Susan
authors: S
authors: Fishbain
authors: 1] Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA. [2] Frontier Research Core for Life Sciences, University of Toyama, Toyama, Japan.
authors: Tomonao
authors: T
authors: Inobe
authors: Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
authors: Eitan
authors: E
authors: Israeli
authors: Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors: Sreenivas
authors: S
authors: Chavali
authors: 1] Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA. [2] Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
authors: Houqing
authors: H
authors: Yu
authors: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA.
authors: Grace
authors: G
authors: Kago
authors: Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors: M Madan
authors: MM
authors: Babu
authors: 1] Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, USA. [2] Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA. [3].
authors: Andreas
authors: A
authors: Matouschek
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000502:physiology*; D017510:Protein Folding; D059748:Proteolysis; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D020539:Sequence Analysis, Protein; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C490846:RAD23 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C577449:CDC34 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex
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