Derlin-1

In 2004 the DERL1 gene was discovered independently by two research groups when they were exploring the machinery of retrotranslocation in the ER in the cell. One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Harvard Medical School, Boston, Massachusetts. Another evidence of the DERL1 gene was discovered by Professor Hidde L. Ploegh and his research group who is also at Harvard Medical School, Boston, Massachusetts. As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996, it was named after the yeast gene. == Gene location ==

The human DERL1 gene is located on the long (q) arm of chromosome 8 at region 2 band 4, from base pair 123,013,164 to 123,042,423 (Build GRCh37/hg19) (map). == Function and mechanism ==

Rerouting factor during ER stress ER stress is caused by an accumulation of unfolded or misfolded proteins in ER and is critical for cell function. The accumulation of unfolded and misfolded proteins activates an unfolded protein response (UPR) which regulate the homeostasis of the cell. One of the strategies cells possess to ER stress as a quality control system is the ERAD pathway, Under ER stress, the carboxyl-terminus region of derlin-1 captures specific misfolded proteins in the ER lumen. Derlin-1 also interacts with VIMP, an ER membrane protein that recruits the cytosolic ATPase p97 and its cofactor. This process is referred to as retrotranslocation. Hence, one of the functions of derlin-1 is to reroute specific misfolded protein to the cytosol for their degradation. Derlin-1 channel holds a short, large transmembrane funnel in the center of tetramer with a diameter about 11-13 angstrom, which might serve as a permeation pathway for misfolded protein substrates in ERAD. Each protomer in human Derlin-1 tetramer shares a high structural similarity with yeast DER1 protein or other rhomboid members. However, this channel architecture makes human derlin-1 different from other known rhomboid structures and implies its centraal role in mammalian ERAD retrotranslocation. Further structural studies showed that Derlin-1 tetramer could form a ERAD complex with AAA ATPase p97, and the conformation of Derlin-1 channel could be changed upon the ATP hydrolysis in p97 from a trans-ER membrane channel into a U-shaped half channel with an open to the lipidic environment of ER membrane. This complex structure suggests that the retrotranslocation activity of Derlin-1 could be powered by p97. == Clinical significance ==

Derlin 1 (DERL1) is up-regulated in metastatic canine mammary tumors as part of the unfolded protein response. == Interactions ==

Derlin-1 has been shown to interact with the following proteins: • HRD1 • VIMP • US11 == See also ==