title: How a disordered ubiquitin ligase maintains order in nuclear protein homeostasis.
abstract: Cells use protein quality control (PQC) systems to protect themselves from potentially harmful misfolded proteins. Many misfolded proteins are repaired by molecular chaperones, but irreparably damaged proteins must be destroyed. Eukaryotes predominantly destroy these abnormally folded proteins through the ubiquitin-proteasome pathway, which requires compartment-specific ubiquitin ligase complexes that mark substrates with ubiquitin for proteasome degradation. In the yeast nucleus, misfolded proteins are targeted for degradation by the ubiquitin ligase San1, which binds misfolded nuclear proteins directly and does not appear to require chaperones for substrate binding. San1 is also remarkably adaptable, as it is capable of ubiquitinating a structurally diverse assortment of abnormally folded substrates. We attribute this adaptability to San1's high degree of structural disorder, which provides flexibility and allows San1 to conform to differently shaped substrates. Here we review our recent work characterizing San1's distinctive mode of substrate recognition and the associated implications for PQC in the nucleus.
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Rosenbaum
authors.forename: Richard G
authors.initials: RG
authors.lastname: Gardner
mesh_terms: D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D018832:Molecular Chaperones; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; C500396:SAN1 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex