Proteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction.
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.
Ponting
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MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. Chris.Ponting@anat.ox.ac.uk
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry; D016208:Databases, Factual; D004721:Endoplasmic Reticulum / Q000737:chemistry* / Q000378:metabolism*; D005656:Fungal Proteins / Q000737:chemistry; D006360:Heat-Shock Proteins; D008390:Markov Chains; D008562:Membrane Glycoproteins / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry; D026901:Membrane Transport Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D020365:RNA Helicases; D012097:Repressor Proteins / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D012984:Software; D013329:Structure-Activity Relationship
C109280:CUE1 protein, S cerevisiae; D002352:Carrier Proteins; D005656:Fungal Proteins; C104622:HRD3 protein, S cerevisiae; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D012097:Repressor Proteins; C074215:SEC63 protein, S cerevisiae; C088668:SEC72 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C104158:BRR2 protein, S cerevisiae; D020365:RNA Helicases