Micrograph of rough endoplasmic reticulum network around the
nucleus (shown in the lower right-hand area of the picture). Dark small circles in the network are
mitochondria.
The endoplasmic reticulum (ER) is a part of a 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 (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as
cisternae (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer
nuclear membrane. The endoplasmic reticulum is not found in
red blood cells, or
spermatozoa.
The two types of ER share many of the same
proteins and engage in certain common activities such as the synthesis of certain
lipids and
cholesterol. Different types of
cells contain different ratios of the two types of ER depending on the activities of the cell. RER is found mainly toward the nucleus of cell and SER towards the cell membrane or plasma membrane of cell.
The ER was observed by
light microscopy by Garnier in 1897, who coined the term ergastoplasm.[2][3] The lacy membranes of the endoplasmic reticulum were first seen by
electron microscopy in 1945 by
Keith R. Porter,
Albert Claude, and Ernest F. Fullam.[4] Later, the word reticulum, which means "network", was applied by Porter in 1953 to describe this fabric of membranes.[5]
Structure
1Nucleus2Nuclear pore3 Rough endoplasmic reticulum (RER)4 Smooth endoplasmic reticulum (SER)5Ribosome on the rough ER6Proteins that are transported7 Transport
vesicle8Golgi apparatus9 Cis face of the Golgi apparatus10 Trans face of the Golgi apparatus11 Cisternae of the Golgi apparatus3D rendering of endoplasmic reticulum
The general structure of the endoplasmic reticulum is a network of membranes called
cisternae. These sac-like structures are held together by the
cytoskeleton. The
phospholipid membrane encloses the cisternal space (or lumen), which is continuous with the
perinuclear space but separate from the
cytosol. The functions of the endoplasmic reticulum can be summarized as the synthesis and export of proteins and membrane lipids, but varies between ER and cell type and cell function. The quantity of both rough and smooth endoplasmic reticulum in a cell can slowly interchange from one type to the other, depending on the changing metabolic activities of the cell. Transformation can include embedding of new proteins in membrane as well as structural changes. Changes in protein content may occur without noticeable structural changes.[6][7]
Rough endoplasmic reticulum
A 2-minute animation showing how a protein destined for the
secretory pathway is synthesized and secreted into the rough endoplasmic reticulum, which appears at the upper right approximately halfway through the animation
The surface of the rough endoplasmic reticulum (often abbreviated RER or rough ER; also called granular endoplasmic reticulum) is studded with protein-manufacturing
ribosomes giving it a "rough" appearance (hence its name).[8] The binding site of the ribosome on the rough endoplasmic reticulum is the
translocon.[9] However, the ribosomes are not a stable part of this organelle's structure as they are constantly being bound and released from the membrane. A ribosome only binds to the RER once a specific protein-nucleic acid complex forms in the cytosol. This special complex forms when a free ribosome begins
translating the
mRNA of a protein destined for the
secretory pathway.[10] The first 5–30
amino acids polymerized encode a
signal peptide, a molecular message that is recognized and bound by a
signal recognition particle (SRP). Translation pauses and the ribosome complex binds to the RER
translocon where translation continues with the
nascent (new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signal
peptidase), which removes the signal peptide. Ribosomes at this point may be released back into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons.[11]
The membrane of the rough endoplasmic reticulum is in the form of large double-membrane sheets that are located near, and continuous with, the outer layer of the
nuclear envelope.[12] The double membrane sheets are stacked and connected through several right- or left-handed helical ramps, the "Terasaki ramps", giving rise to a structure resembling a
parking garage.[13][14] Although there is no continuous membrane between the endoplasmic reticulum and the
Golgi apparatus, membrane-bound
transport vesicles shuttle proteins between these two compartments.[15] Vesicles are surrounded by
coating proteins called COPI and COPII.
COPII targets vesicles to the Golgi apparatus and
COPI marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the
Golgi complex to
target new proteins to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called
membrane contact sites, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules.[16][17]
The rough endoplasmic reticulum is key in multiple functions:
Manufacture of
secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving
clathrin and paired basic amino acids in the
signal peptide.
Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes.
Rab proteins are key in targeting the membrane;
SNAP and
SNARE proteins are key in the fusion event.
Initial
glycosylation as assembly continues. This is N-linked (O-linking occurs in the Golgi).
N-linked glycosylation: If the protein is properly folded,
oligosaccharyltransferase recognizes the AA sequence
NX
S or
NX
T (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-N-acetylglucosamine, 9-branching
mannose, and 3-
glucose at the end) to the side-chain
nitrogen of Asn.
Smooth endoplasmic reticulum
Electron micrograph showing smooth ER (arrow) in mouse tissue, at 110,510× magnification
In most cells the smooth endoplasmic reticulum (abbreviated SER) is scarce. Instead there are areas where the ER is partly smooth and partly rough, this area is called the transitional ER. The transitional ER gets its name because it contains ER exit sites. These are areas where the transport vesicles which contain lipids and proteins made in the ER, detach from the ER and start moving to the
Golgi apparatus. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions.[6] It synthesizes
lipids,
phospholipids,[19][20][21] and
steroids. Cells which secrete these products, such as those in the
testes,
ovaries, and
sebaceous glands have an abundance of smooth endoplasmic reticulum.[22] It also carries out the metabolism of carbohydrates, detoxification of natural metabolism products and of alcohol and drugs, attachment of receptors on cell membrane proteins, and
steroid metabolism.[23] In muscle cells, it regulates
calcium ion concentration. Smooth endoplasmic reticulum is found in a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmic reticulum also contains the enzyme
glucose-6-phosphatase, which converts
glucose-6-phosphate to glucose, a step in
gluconeogenesis. It is connected to the
nuclear envelope and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance.[12] In some cells, there are dilated areas like the sacs of rough endoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to be devoted to the action or storage of key enzymes and the products of these enzymes.[citation needed]
Sarcoplasmic reticulum
Skeletal muscle fiber, with sarcoplasmic reticulum colored in blue
The sarcoplasmic reticulum (SR), from the Greek σάρξ sarx ("flesh"), is smooth ER found in
muscle cells. The only structural difference between this organelle and the smooth endoplasmic reticulum is the composition of proteins they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while the sarcoplasmic reticulum stores calcium ions and pumps them out into the sarcoplasm when the muscle fiber is stimulated.[24][25] After their release from the sarcoplasmic reticulum, calcium ions interact with contractile proteins that utilize ATP to shorten the muscle fiber. The sarcoplasmic reticulum plays a major role in
excitation-contraction coupling.[26]
Functions
The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called
cisternae and the transport of synthesized proteins in
vesicles to the
Golgi apparatus. Rough endoplasmic reticulum is also involved in protein synthesis. Correct folding of newly made proteins is made possible by several endoplasmic reticulum
chaperone proteins, including
protein disulfide isomerase (PDI), ERp29, the
Hsp70 family member
BiP/Grp78,
calnexin,
calreticulin, and the peptidylprolyl isomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus – unfolded proteins cause an
unfolded protein response as a stress response in the ER. Disturbances in
redox regulation, calcium regulation, glucose deprivation, and viral infection[27] or the over-expression of proteins[28] can lead to
endoplasmic reticulum stress response (ER stress), a state in which the folding of proteins slows, leading to an increase in
unfolded proteins. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.[29]
Protein transport
Secretory proteins, mostly
glycoproteins, are moved across the endoplasmic reticulum membrane. Proteins that are transported by the endoplasmic reticulum throughout the cell are marked with an address tag called a
signal sequence. The N-terminus (one end) of a
polypeptide chain (i.e., a protein) contains a few
amino acids that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the
translocon, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport
vesicles and moved along the
cytoskeleton toward their destination. In human fibroblasts, the ER is always co-distributed with microtubules and the depolymerisation of the latter cause its co-aggregation with mitochondria, which are also associated with the ER.[30]
The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of the eukaryotic cell. The majority of its resident proteins are retained within it through a retention
motif. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences are
KDEL for lumen-located proteins and
KKXX for transmembrane proteins.[31] However, variations of KDEL and KKXX do occur, and other sequences can also give rise to endoplasmic reticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDEL (
1,
2 and
3) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.[32]
Bioenergetics regulation of ER ATP supply by a CaATiER mechanism
Ca2+-antagonized transport into the endoplasmic reticulum (CaATiER) model
The endoplasmic reticulum does not harbor an ATP-regeneration machinery, and therefore requires ATP import from mitochondria. The imported ATP is vital for the ER to carry out its house keeping cellular functions, such as for protein folding and trafficking.[33]
The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized,[34] and the mitochondria supply ATP to the ER through a Ca2+-antagonized transport into the ER (CaATiER) mechanism.[35] The CaATiER mechanism shows sensitivity to cytosolic Ca2+ ranging from high nM to low μM range, with the Ca2+-sensing element yet to be identified and validated.[36]
Clinical significance
Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia[37] and consequently peripheral insulin resistance associated with obesity in humans.[38] Human clinical trials also suggested a causal link between obesity-induced increase in insulin secretion and peripheral insulin resistance.[39]
The
unfolded protein response (UPR) is a
cellular stress response related to the endoplasmic reticulum.[42] The UPR is activated in response to an accumulation of unfolded or misfolded
proteins in the
lumen of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein
translation, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular
chaperones involved in
protein folding. Sustained overactivation of the UPR has been implicated in
prion diseases as well as several other
neurodegenerative diseases and the inhibition of the UPR could become a treatment for those diseases.[43]
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