Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a membrane protein that in humans is encoded by the DERL1gene.[5][6][7][8] Derlin-1 is located in the membrane of the endoplasmic reticulum (ER) and is involved in retrotranslocation of specific misfolded proteins and in ER stress.[6][8] Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues.[9] The protein belongs to the Derlin-family proteins (also called derlins) consisting of derlin-1, derlin-2 and derlin-3 that are components in the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER,[6][8][10][11] and are named ‘der’ for their ‘Degradation in the ER’.[12] Derlin-1 is a mammalian homologue of the yeast DER1 protein, a protein involved in the yeast ERAD pathway.[6][8][12] Moreover, derlin-1 is a member of the rhomboid-like clan of polytopic membrane proteins.[10]
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.[6][8] One evidence for the existence of DERL1 was provided by Professor Tom A. Rapoport and his research group at Harvard Medical School, Boston, Massachusetts.[8] 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.[6] As the mammalian DERL1 gene was found to be a homologue of the yeast DER1 gene found in 1996,[12] it was named after the yeast gene.[6][8]
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).[9]
Under ER stress, the carboxyl-terminus region of derlin-1 captures specific misfolded proteins in the ER lumen.[22] Derlin-1 also interacts with VIMP, an ER membrane protein that recruits the cytosolic ATPase p97 and its cofactor.[8] 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.[23] 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.[6][8][22] Prior to the cytosolic degradation, the retrotranslocated misfolded proteins interacts with HRDI E3 ubiquitin ligase.[22] This ligase ubiquitinates the misfolded proteins promoting their degradation in the cytosol by the ubiquitin-protease system (UPS).[22] 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.[24] 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.[25] 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.[26] 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.[27][28][29]
Interactions
Derlin-1 has been shown to interact with the following proteins:
↑ Tan X, He X, Jiang Z, Wang X, Ma L, Liu L, etal. (October 2015). "Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation". Molecular and Cellular Biochemistry. 408 (1–2): 205–13. doi:10.1007/s11010-015-2496-x. PMID26173415. S2CID18437543.
↑ Mao M, Zhang J, Jiang J (January 2018). "Overexpression of Derlin-1 is Associated with Poor Prognosis in Patients with Non-small Cell Lung Cancer". Annals of Clinical and Laboratory Science. 48 (1): 29–34. PMID29530993.
↑ Kim I, Xu W, Reed JC (December 2008). "Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities". Nature Reviews. Drug Discovery. 7 (12): 1013–30. doi:10.1038/nrd2755. PMID19043451. S2CID7652866.
Schulze A, Standera S, Buerger E, Kikkert M, van Voorden S, Wiertz E, etal. (December 2005). "The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway". Journal of Molecular Biology. 354 (5): 1021–7. doi:10.1016/j.jmb.2005.10.020. PMID16289116.
Crawshaw SG, Cross BC, Wilson CM, High S (2007). "The oligomeric state of Derlin-1 is modulated by endoplasmic reticulum stress". Molecular Membrane Biology. 24 (2): 113–20. doi:10.1080/09687860600988727. PMID17453418. S2CID44903284.
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