Means of self-preservation: How an intrinsically disordered ubiquitin-protein ligase averts self-destruction

Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA.
Molecular biology of the cell (Impact Factor: 4.47). 01/2013; 24(7). DOI: 10.1091/mbc.E12-11-0811
Source: PubMed


Ubiquitin-protein ligases (E3s) that ubiquitinate substrates for proteasomal degradation are often in the position of ubiquitinating themselves due to interactions with a charged ubiquitin-conjugating enzyme (E2). This can mediate the E3's proteasomal degradation. Many E3s have evolved means to avoid autoubiquitination including protection by partner or substrate binding, preventative modifications, and deubiquitinating enzyme reversal of ubiquitination. Here, we describe another adaptation for E3 self-protection discovered while exploring San1, which ubiquitinates misfolded nuclear proteins in yeast for proteasomal degradation. San1 is highly disordered in its substrate-binding regions N- and C-terminal to its RING domain. In cis autoubiquitination could occur if these flexible regions come in proximity to the E2. San1 prevents this by containing no lysines in its disordered regions, thus the canonical residue used for ubiquitin attachment has been selectively eliminated. San1's target substrates have lost their native structures and expose hydrophobicity. To avoid in trans autoubiquitination, San1 possesses little concentrated hydrophobicity in its disordered regions, thus the feature San1 recognizes in misfolded substrates has also been selectively eliminated. Overall, the presence of key residues in San1 have been evolutionarily minimized to avoid self-destruction either in cis or in trans. Our work expands the ways E3s protect themselves from autoubiquitination.

Full-text preview

Available from: PubMed Central
  • [Show abstract] [Hide abstract]
    ABSTRACT: The accumulation and aggregation of misfolded proteins is the primary hallmark for more than 45 human degenerative diseases. These devastating disorders include Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. Over 15 degenerative diseases are associated with the aggregation of misfolded proteins specifically in the nucleus of cells. However, how the cell safeguards the nucleus from misfolded proteins is not entirely clear. In this review, we discuss what is currently known about the cellular mechanisms that maintain protein homeostasis in the nucleus and protect the nucleus from misfolded protein accumulation and aggregation. In particular, we focus on the chaperones found to localize to the nucleus during stress, the ubiquitin-proteasome components enriched in the nucleus, the signaling systems that might be present in the nucleus to coordinate folding and degradation, and the sites of misfolded protein deposition associated with the nucleus.
    No preview · Article · Dec 2013 · Cellular and Molecular Life Sciences CMLS
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The current literature on intrinsically disordered proteins is overwhelming. To keep interested readers up to speed with this literature, we continue a “Digested Disorder” project and represent a series of reader’s digest type articles objectively representing the research papers and reviews on intrinsically disordered proteins. The only 2 criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest issue covers papers published during the period of April, May, and June of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.
    Preview · Article · May 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: UPS (ubiquitin-proteasome system) is a kind of fundermental ubiquitin-mediated proteolysis pathway that widely exists in eukaryotes. In Arabidopsis, ASK (Arabidopsis SKP1-LIKE) encodes a subunit of SCF E3 ligase, which functions as a connector in SCF complexes in Arabidopsis. In recent years, the scientists conducted various research in expression pattern and gene function for ASK gene as well as it's homologous. This review summarizes these progresses on the expression pattern, regulation mechanism, interaction with F-box protein and gene evolution source. The existing results highlight these progresses and suggest that ASK genes have different expression level and expression patterns. They are widely expressed in Arabidopsis and play very important roles in many development and physiological processes.
    No preview · Article · Jun 2014 · Zhiwu Shengli Xuebao/Plant Physiology Journal
Show more