Derlin-1 also known as degradation in endoplasmic reticulum protein 1 is a

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

that in humans is encoded by the ''DERL1''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. Derlin-1 is located in the membrane of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) and is involved in retrotranslocation of specific misfolded proteins and in ER stress. Derlin-1 is widely expressed in thyroid, fat, bone marrow and many other tissues. The protein belongs to the Derlin-family proteins (also called derlins) consisting of derlin-1,

derlin-2 Derlin-2 is a protein that in humans is encoded by the ''DERL2'' gene. See also * Derlin-1 * Derlin-3 Derlin-3 is a protein that in humans is encoded by the ''DERL3'' gene. See also * Derlin-1 * Derlin-2 Derlin-2 is a protein that in hum ...

and

derlin-3 Derlin-3 is a protein that in humans is encoded by the ''DERL3'' gene. See also * Derlin-1 * Derlin-2 Derlin-2 is a protein that in humans is encoded by the ''DERL2'' gene. See also * Derlin-1 * Derlin-3 Derlin-3 is a protein that in huma ...

that are components in the endoplasmic reticulum-associated protein degradation (ERAD) pathway. The derlins mediate degradation of misfolded lumenal proteins within ER, and are named ‘der’ for their ‘Degradation in the ER’. Derlin-1 is a mammalian homologue of the yeast '' DER1'' protein, a protein involved in the yeast ERAD pathway. Moreover, derlin-1 is a member of the

rhomboid Traditionally, in two-dimensional geometry, a rhomboid is a parallelogram in which adjacent sides are of unequal lengths and angles are non-right angled. A parallelogram with sides of equal length (equilateral) is a rhombus but not a rhomboid. ...

-like clan of polytopic membrane proteins. Overexpression of derlin-1 are associated with many cancers, including

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel mo ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...

bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become mali ...

and

non-small cell lung cancer Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...

Discovery

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 Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA ...

at region 2 band 4, from

base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

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 The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

(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, by which Derlin-1 is a component of. As a part of an ER membrane protein complex (that includes VIMP, SEL1,

HRD1 E3 ubiquitin-protein ligase synoviolin is an enzyme that in humans is encoded by the ''SYVN1'' gene. Function This gene encodes a protein involved in endoplasmic reticulum (ER)-associated degradation. The encoded protein removes unfolded protei ...

, and

HERP Herpetology (from Greek ἑρπετόν ''herpetón'', meaning "reptile" or "creeping animal") is the branch of zoology concerned with the study of amphibians (including frogs, toads, salamanders, newts, and caecilians (gymnophiona)) and rept ...

) derlin-1 detects misfolded proteins in ER and mediate them for their degradation in 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. 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

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

ates 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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with the following proteins: * HRD1 * VIMP * US11