Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins

Abstract

The endoplasmic reticulum (ER) contains a highly effective protein quality control system eliminating malfolded proteins by a mechanism called ER-associated protein degradation (ERAD). Here, we unravel the topology of Der1p, a previously identified component of the ERAD system. Der1p contains four transmembrane domains, its N- and C-terminus protrude into the cytoplasm and contribute to its function. Additionally, we describe a yeast homologue of Der1p, Dfm1p, which does not seem to be involved in ERAD. In contrast, a Caenorhabditis elegans orthologue of Der1p, R151.6, is capable of complementing der1-defective phenotypes in yeast.

The virulence of the opportunistic fungal pathogenAspergillus fumigatusrequires cooperation between the endoplasmic reticulum-associated degradation pathway (ERAD) and the unfolded protein response (UPR)

“…The two proteins share 24% identity and 49% similarity and have the same predicted four transmembrane helices followed by a short cytosolic C-terminal domain. 24 The presence of a single predicted intron in the A. fumigatus derA gene was confirmed by PCR amplification of the full-length cDNA (data not shown). The derA gene was deleted from A. fumigatus by replacing it with a hygromycin resistance cassette, resulting in truncation of a 9 kb NsiI fragment containing the derA gene (probe 1, Fig.…”

Inactive rhomboid proteins: New mechanisms with implications in health and disease

“…1), block both, protease and pseudoprotease function [6,7,59,60]. Likewise, the serine-59-leucine loss-of-function mutation encoded by the yeast der1-2 allele found in the original genetic screen [39,47], affects a conserved residue that derlins share with most rhomboid proteases [7]. These striking similarities in the L1 loop strengthen the hypothesis of structural conservation between secretory pathway rhomboids and derlins.…”

“…In a related manner, the second yeast derlin protein Dfm1 (for 'Der1-like family member 1') is a key component of several ERAD complexes, functionally interacting with either Hrd1, the second yeast ERAD E3 ubiquitin ligase Doa10 [45], or with the aspartyl intramembrane protease Ypf1 [37,46]. Interestingly, whereas Der1 is required for turnover of soluble ERAD substrates but is not essential for degradation of TM proteins [39,43,47,48], the few known Dfm1 clients are all membrane proteins [45,46] [43,45,49], suggesting that redundant degradation routes exist.…”

Control of p97 function by cofactor binding

“…The SHP box binding motif (also called binding site 1, BS1) was initially identified in the yeast proteins Shp1 (the yeast ortholog of p47), Ufd1, Wss1 and the Derlin homolog Dfm1 [75,76], as well as in mammalian p47 and UFD1 [50]. It is a short hydrophobic sequence stretch containing two invariant glycine residues and is characterized by the consensus sequence FxGxGx 2 h (x, any amino acid, h, hydrophobic amino acid) ( Fig.…”