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. The interaction of derlin-1 with p97 via VIMP is essential for export of misfolded proteins. p97 is required for the transport of the misfolded proteins through the ER membrane and back to the cytosolic side for their degradation. 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. Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase. This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS). Currently, the molecular mechanism by which derlin-1 reroutes the misfolded proteins from ER to their degradation are not fully understood. The structure of Derlin-1 The cryo-EM analysis revealed that human Derlin-1 forms a tetrameric channel across the ER membrane. 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 centrtal role in mammalian ERAD retrotranslocation. 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 Derlin-2 Derlin-3 References Further reading