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 hithertoundetected homologues of proteins that regulate the endoplasmic reticulum (ER)-associated degradation pathway . The translocon-associated subunit Sec63p(Sec = secretory) was shown to co ntain a domain of unknown function found twice in several Brr2p-like RNA he licases (Brr2 = bad response to refrigeration 2). Additionally, Cue1p (Cue = coupling of ubiquitin conjugation to ER degradation), a yeast protein tha t recruits the ubiquitin-conjugating (UBC) enzyme Ubc7p to an ER-associated complex, was found to be one of a large family of putative scaffolding-dom ain-containing proteins that include the autocrine motility factor receptor and fungal Vps9p (Vps = vacuolar protein sorting). Two other yeast translo con-associated molecules, Sec72p and Hrd3p (Hrd = 3-hydroxy-3-methylglutary l-CoA reductase degradation), were shown to contain multiple tetratricopept ide-repeat-like sequences. From this observation it is suggested that Sec72 p associates with a heat-shock protein, Hsp70, in a manner analogous to tha t known for Hop (Hsp70/Hsp90 organizing protein). Finally, the luminal port ion of Ire1p (Ire = high inositol-requiring), thought to convey the sensing function of this transmembrane kinase and endoribonuclease, was shown to c ontain repeats similar to those in beta -propeller proteins. This finding h ints at the mechanism by which Ire1p may sense extended unfolded proteins a t the expense of compact folded molecules.