Proteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction

Research output: Contribution to journalArticlepeer-review

Abstract

Sequence database searches, using iterative-profile and Hidden-Markov-model approaches, were used to detect hitherto-undetected homologues of proteins that regulate the endoplasmic reticulum (ER)-associated degradation pathway. The translocon-associated subunit Sec63p (Sec=secretory) was shown to contain a domain of unknown function found twice in several Brr2p-like RNA helicases (Brr2=bad response to refrigeration 2). Additionally, Cue1p (Cue=coupling of ubiquitin conjugation to ER degradation), a yeast protein that recruits the ubiquitin-conjugating (UBC) enzyme Ubc7p to an ER-associated complex, was found to be one of a large family of putative scaffolding-domain-containing proteins that include the autocrine motility factor receptor and fungal Vps9p (Vps=vacuolar protein sorting). Two other yeast translocon-associated molecules, Sec72p and Hrd3p (Hrd=3-hydroxy-3-methylglutaryl-CoA reductase degradation), were shown to contain multiple tetratricopeptide-repeat-like sequences. From this observation it is suggested that Sec72p associates with a heat-shock protein, Hsp70, in a manner analogous to that known for Hop (Hsp70/Hsp90 organizing protein). Finally, the luminal portion of Ire1p (Ire=high inositol-requiring), thought to convey the sensing function of this transmembrane kinase and endoribonuclease, was shown to contain repeats similar to those in beta-propeller proteins. This finding hints at the mechanism by which Ire1p may sense extended unfolded proteins at the expense of compact folded molecules.

Original languageEnglish
Pages (from-to)527-35
Number of pages9
JournalBiochemical Journal
Volume351 Pt 2
Publication statusPublished - 15 Oct 2000

Keywords

  • Amino Acid Sequence
  • Carrier Proteins
  • Databases, Factual
  • Endoplasmic Reticulum
  • Fungal Proteins
  • Heat-Shock Proteins
  • Markov Chains
  • Membrane Glycoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Models, Biological
  • Molecular Sequence Data
  • Protein Folding
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases
  • RNA Helicases
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Software
  • Structure-Activity Relationship

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