Theendoplasmic reticulum (ER) is a part of a transportation system of theeukaryotic cell, and has many other important functions such asprotein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little net". It is a type oforganelle made up of two subunits –rough endoplasmic reticulum (RER), andsmooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known ascisternae (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outernuclear membrane. The endoplasmic reticulum is not found inred blood cells, orspermatozoa.
There are two types of ER that share many of the sameproteins and engage in certain common activities such as the synthesis of certainlipids andcholesterol. Different types ofcells contain different ratios of the two types of ER depending on the activities of the cell. RER is found mainly toward the nucleus of the cell and SER towards the cell membrane or plasma membrane of the cell.
1Nucleus2Nuclear pore3 Rough endoplasmic reticulum (RER)4 Smooth endoplasmic reticulum (SER)5Ribosome on the rough ER6Proteins that are transported7 Transportvesicle8Golgi apparatus9 Cis face of the Golgi apparatus10 Trans face of the Golgi apparatus11 Cisternae of the Golgi apparatus
The general structure of the endoplasmic reticulum is a network of membranes calledcisternae. These sac-like structures are held together by thecytoskeleton. Thephospholipid membrane encloses the cisternal space (or lumen), which is continuous with theperinuclear space but separate from thecytosol. 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.[5][6]
A 2-minute animation showing how a protein destined for thesecretory 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 abbreviatedRER orrough ER; also calledgranular endoplasmic reticulum) is studded with protein-manufacturingribosomes giving it a "rough" appearance (hence its name).[7] The binding site of the ribosome on the rough endoplasmic reticulum is thetranslocon.[8] 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 beginstranslating themRNA of a protein destined for thesecretory pathway.[9] The first 5–30amino acids polymerized encode asignal peptide, a molecular message that is recognized and bound by asignal recognition particle (SRP). Translation pauses and the ribosome complex binds to the RERtranslocon where translation continues with thenascent (new) protein forming into the RER lumen and/or membrane. The protein is processed in the ER lumen by an enzyme (a signalpeptidase), 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.[10]
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 thenuclear envelope.[11] 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 aparking garage.[12][13] Although there is no continuous membrane between the endoplasmic reticulum and theGolgi apparatus, membrane-boundtransport vesicles shuttle proteins between these two compartments.[14] Vesicles are surrounded bycoating proteins called COPI and COPII.COPII targets vesicles to the Golgi apparatus andCOPI marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with theGolgi complex totarget new proteins to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas calledmembrane 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.[15][16]
The rough endoplasmic reticulum is key in multiple functions:
Manufacture ofsecreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involvingclathrin and paired basic amino acids in thesignal 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 andSNARE proteins are key in the fusion event.
Initialglycosylation 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 sequenceNXS orNXT (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-N-acetylglucosamine, 9-branchingmannose, and 3-glucose at the end) to the side-chainnitrogen of Asn.
Electron micrograph showing smooth ER (arrow) in mouse tissue, at 110,510× magnification
In most cells the smooth endoplasmic reticulum (abbreviatedSER) is scarce. Instead there are areas where the ER is partly smooth and partly rough: the transitional ER. The transitional ER gets its name because it contains ER exit sites, areas where the transport vesicles, which contain lipids and proteins made in the ER, detach from the ER and start moving to theGolgi apparatus. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions.[5] It synthesizeslipids,phospholipids,[18][19][20] andsteroids. Cells which secrete these products, such as those in thetestes,ovaries, andsebaceous glands have an abundance of smooth endoplasmic reticulum.[21] 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, andsteroid metabolism.[22] In muscle cells, it regulatescalcium 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 enzymeglucose-6-phosphatase, which convertsglucose-6-phosphate to glucose, a step ingluconeogenesis. It is connected to thenuclear envelope and consists of tubules that are located near the cell periphery. These tubes sometimes branch forming a network that is reticular in appearance.[11] 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]
The sarcoplasmic reticulum (SR), from the Greek σάρξsarx ("flesh"), is smooth ER found inmuscle 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.[23][24] 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 inexcitation-contraction coupling.[25]
The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs calledcisternae and the transport of synthesized proteins invesicles to theGolgi apparatus. Rough endoplasmic reticulum is also involved in protein synthesis. Correct folding of newly made proteins is made possible by several endoplasmic reticulumchaperone proteins, includingprotein disulfide isomerase (PDI), ERp29, theHsp70 family memberBiP/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 anunfolded protein response as a stress response in the ER. Disturbances inredox regulation, calcium regulation, glucose deprivation, and viral infection[26] or the over-expression of proteins[27] can lead toendoplasmic reticulum stress response (ER stress), a state in which the folding of proteins slows, leading to an increase inunfolded proteins. This stress is emerging as a potential cause of damage in hypoxia/ischemia, insulin resistance, and other disorders.[28]
Secretory proteins, mostlyglycoproteins, 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 asignal sequence. The N-terminus (one end) of apolypeptide chain (i.e., a protein) contains a fewamino acids that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via thetranslocon, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transportvesicles and moved along thecytoskeleton 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.[29]
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 retentionmotif. This motif is composed of four amino acids at the end of the protein sequence. The most common retention sequences areKDEL for lumen-located proteins andKKXX for transmembrane proteins.[30] 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 and3) receptors in mammalian cells, and they have a very high degree of sequence identity. The functional differences between these receptors remain to be established.[31]
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.[32]
The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized,[33] and the mitochondria supply ATP to the ER through aCa2+-antagonized transport into the ER (CaATiER) mechanism.[34] TheCaATiER 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.[35]
Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia[36] and consequently peripheral insulin resistance associated with obesity in humans.[37] Human clinical trials also suggested a causal link between obesity-induced increase in insulin secretion and peripheral insulin resistance.[38]
Theunfolded protein response (UPR) is acellular stress response related to the endoplasmic reticulum.[41] The UPR is activated in response to an accumulation of unfolded or misfoldedproteins in thelumen of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting proteintranslation, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecularchaperones involved inprotein folding. Sustained overactivation of the UPR has been implicated inprion diseases as well as several otherneurodegenerative diseases and the inhibition of the UPR could become a treatment for those diseases.[42]
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