What is the Endoplasmic Reticulum?

There are many important functions that are carried by the endoplasmic reticulum like protein folding. In simple words, it is the transportation system of eukaryotic cells. Usually, two units made this organelle i.e., smooth endoplasmic reticulum (SER) and rough endoplasmic reticulum (RER). There is a network between RER and SER i.e., cisternae of RER that are basically membrane-bound sacs interconnected with the SER’s tubular structures. This organelle is found in most eukaryotic cells. The point where the nucleus’s outer membrane ends gives a start to the membrane of the endoplasmic reticulum. Spermatozoa and Red blood cells lack endoplasmic reticulum. There are some functions in which both types of ER take part like in the synthesis of cholesterol and lipid and also share the same proteins. Dependent on the activity of the cell the number of RER and SER can differ in a eukaryotic cell. Usually, SER is present towards the plasma membrane or cell membrane of the cell whereas RER is normally found near the nucleus. Ribosomes are embedded on the outer surface of RER because of which they are named as rough endoplasmic reticulum and their function there is to synthesize protein. In cells like hepatocytes, RER is very important. The function of SER is the synthesis of lipids and ribosomes are absent in them that’s why they are called the smooth endoplasmic reticulum. The SER is responsible for the formation of lipids but not responsible for their metabolism nor for the detoxification and production of steroid hormones. In cells of gonads cells and the mammalian liver, SER is present in a huge amount. For the first time, it was observed in 1897 by Garnier under a light microscope and he named it Ergastoplasm. Then Keith R. Porter, Ernest F. Fullam, and Albert Claude under an electronic microscope first time saw lacy members of the endoplasmic reticulum in 1945. To describe fabrics of members Porter in 1953 gave that network a name i.e., reticulum.

Cisternae is a network of membranes that is the common structure of the endoplasmic reticulum. The cytoskeleton is the one who had held these sac-like structures together. Perinuclear space is separated from cytosol while the cell membrane or the phospholipid membrane encage cisternal space. Synthesis of membrane lipids and export of protein is the main function of the endoplasmic reticulum. Between the ER, cell function, and cell type these functions can vary. SER and RER are interconvertible into each cell. The change of RER into SER and vice-versa depends on the change in the metabolic activities of the cell. When there is an interchange between SER and RER then there is the addition of new protein on their surface and the structure also changes. Sometimes without the change in structure, there is a change in proteins.

Anatomy of Rough Endoplasmic Reticulum

There is a rough appearance on the outer surface of the endoplasmic reticulum due to the presence of ribosomes which has the function of synthesis of proteins. Translocon is the site of attachment for ribosomes in ER. As they are used to release and bound from the membrane constantly so they are not a permanent organelle of the endoplasmic reticulum. There is a specific complex of protein-nucleic acid which is formed in the cytosol. The formation of this complex in the cytosol is an indication that ribosomes will bind to RER. The ribosome can bind only when this complex is formed. For the secretory pathway, there is a protein which is needed to be translated by ribosomes when the mRNA of this protein starts getting translated by the ribosomes then the ribosome will get attached to RER. For a message to get recognized and bound to a signal recognition particle first 5-30 amino acids are polymerized to form a single peptide. New proteins are formed at the RER membrane when the ribosome complex attaches there after the translation pauses in the cytosol. There’s an enzyme in ER which removes the single peptide while processing a protein. After the work is done ribosomes are released back into the cytosol. Sometimes ribosomes that are non-translating stay embedded in the membrane of ER. The endoplasmic reticulum has double membrane sheets which run along the outer membrane. There are many helical ramps located left and right in this double membrane because of which the membrane looks like multi-story car parking. These helical ramps are known as ‘Terasaki ramps. In ER and Golgi apparatus there is no continuous membrane but for transport in between them, they have shuttle proteins which are transport vesicles. COPI and COPII are the two coating proteins that surround vesicles. COPI has the function of bringing vesicles back to ER whereas COPII is responsible for transporting the vesicles to the Golgi apparatus. To deliver new proteins to their final destinations both ER and Golgi apparatus work together. Membrane contact sites are located at the peripheral membrane of the endoplasmic reticulum which also transports the proteins. These sites are associated with organelles present near ER. Through this method, small molecules and lipids are transported to their assigned location.

Ribosomes

Ribosomes are the macromolecular machines due to which there are two types of the endoplasmic reticulum. Ribosomes are also known as palate granules. The synthesis of protein is the main function of ribosomes. They have a granular appearance present on the endoplasmic reticulum. Two major components form ribosomes i.e., a large subunit and a small subunit. Many ribosomal proteins and one or more ribosomal RNA are present in each subunit. The transitional apparatus are the ribosomes and the additional molecules. 
There are two types of ribosomes 

• Eukaryotic ribosomes– In their cytosol, they have 80S ribosomes. The larger subunit is the 60S and the smaller subunit is 40S. Here S represent its unit i.e., Svedberg. There are 33 proteins and 18S RNA present in the 40S subunit. There is 5S RNA, 28S RNA, and a5.8s RNA in the large subunit along with 46 proteins.
• Prokaryotic ribosomes-It contains 70S ribosomes. Subunits that are present in prokaryotic ribosomes are the 50S and 30S. In E.coli, has 21 proteins that are bound to 16S RNA. 31 proteins, 23S RNA subunit, and 5S RNA are the components of the large subunit. 

Anatomy of Smooth Endoplasmic Reticulum

SER is very uncommon in most cells. Transitional ER are the areas where the ER is partially SER and partially RER. ER exit sites are located at transitional ER that’s why it is named so. The proteins that are to be transported to the Golgi apparatus stay in this region after getting detach from ER and before their entry into the Golgi apparatus. The cells which have a greater number of Smooth ER are some specialized cells that have many functions to perform in an organism. Steroid synthesis and lipid synthesis is performed by smooth ER. Cells of the testis, sebaceous gland, and ovaries that produce these products like lipids and steroids have a huge number of the endoplasmic reticulum. Calcium ion concentration is regulated by SER in muscles. In plants and animals, there are different types of SER that serve different functions. In gluconeogenesis where in a step glucose-6-phosphate is converted into glucose. This glucose-6-phosphate is present in SER. Near the cell periphery, the SER is connected to the nuclear envelope having a lot of tubules. The network of these tubules gives a reticular appearance. For the storage of the key enzymes and their products, the surface of SER can be increased. For the first time, sarcoplasmic reticulum was found in muscle cells. There are some proteins that are present in the sarcoplasmic reticulum and not in SER. This is the only difference they have in them. These proteins, perform different functions. SER performs the function of synthesis whereas the sarcoplasmic reticulum performs the function of storage of calcium ions which are pumped when the stimulation occurs in muscles. In excitation-contraction coupling, the sarcoplasmic reticulum plays a very crucial role.

Functions

There are many functions that are performed by the endoplasmic reticulum. First of all, the folding of proteins is done by ER in cisternae which is a sac-like structure used for the same. Transportation of proteins synthesized by enzymes in ER to Golgi apparatus is done by ER. Protein synthesis is also done by RER. Chaperone proteins, which entail ERp29, Hsp70 family member BiP/Grp78, calnexin, protein disulfide isomerase (PDI), etc. are responsible for the correct folding of new proteins. A stress response is generated by unfolded proteins in ER and only the perfectly folded proteins are carried to the Golgi apparatus. There are many more reasons for causing a stress response in ER like a disturbance in calcium regulation, glucose deprivation, viral infection, redox regulation, etc. Damage in hypoxia and insulin resistance is caused by this stress in ER.

Transport of proteins

Many glycoproteins which are secretory proteins are transported across members of ER. Signal sequences are the proteins that get transported from ER throughout. When polypeptides reach their destination the N-terminal that contains few amino acids are removed. Translocon which is a multiprotein complex helps nascent proteins in reaching ER. Transportation of packed molecules in vesicles to their locations is done by ER. The depolarization of the latter ER is associated with mitochondria and is also distributed along mitochondria. The protein sorting pathway is also a function of ER. It is basically the transportation system of the endoplasmic reticulum. Retention motifs helps resident protein to be retained in ER. At the end of protein sequence, there are four amino acids which form motif. KKXX and KDEL are most popular retention sequences. KXXX is the retention sequence for transmembrane protein and KDEL is the retention sequence for proteins located in the lumen. Endoplasmic reticulum retention is also caused by other sequences caused due to the difference in these sequences. A high degree of sequence identity can be found in mammalian cells where three different receptors of KDEL are present.

Cartier Mechanism

Mitochondria import ATP to ER as ER does not have the machinery to generate ATP. The function of ER i.e., protein trafficking and protein folding are carried out by the ATP which is imported from mitochondria. Through Ca2+ – antagonized transport the ATP is imported into ER through an ATP transporter i.e., SLC35B1/AXER. This transporter is recently cloned. This mechanism is known as the Cartier mechanism.

Calcium metabolism and storage

The endoplasmic reticulum is responsible for the storage of calcium ions. As if it is also responsible for the synthesis and transport of many different biomolecules. The concentration of calcium ions in the lumen of the endoplasmic reticulum is 100-800 micrometers and the concentration outside of ER lumen is approx. 2 millimeters. The concentration of calcium ions in the cytoplasm is approx. 100 nanometer. When the level of calcium ions decreases inside ER then there are few calcium channels that release calcium ions from ER into the cytoplasm. The channels which are responsible for the release of calcium ions are ryanodine receptors and inositol 1,4,5-triphosphate receptors. Calcium ions are released when phosphatidylinositol 4,5 bisphosphate breaks into diacyl-glycerol and IP3. This reaction is stimulated by the activation of the G protein-coupled receptor. With the release of calcium ions the transient level of calcium ions increases. There are some conformational changes in voltage-dependent calcium channels due to the depolarization of t-tubule membranes which leads to the release of calcium ions after activation of RyRs. Sometimes to pump back the calcium ions from cytoplasm through sarcoendoplasmic reticulum calcium ATPases calcium ion leaks from ER to cytosol. Many processes like localization, an association of proteins, functions of organelles or nucleic acids, etc. can be affected by calcium which is a major signaling molecule. A calcium spark is a wave of calcium that moves through the entire cell and the gradient which is formed from where the calcium ions are released. In the cellular signaling of ER, calcium ions play an important role in the reshaping ER.

Clinical Aspects

Obesity, hyperinsulinemia, and abnormal insulin secretion are all caused by supraphysiological and increased ER stress in pancreatic beta cells. According to the result of the trials done on humans, there is a connection found between increased insulin secretion and obesity, and peripheral insulin resistance. The endoplasmic reticulum stress response increases when they’re an abnormality in XBP1. Abnormality in this also causes inflammation problems which leads to Alzheimer’s disease. Crohn’s disease is caused by abnormalities of XBP1. The cellular stress response is caused by unfolded protein response-related endoplasmic reticulum. Functions like degrading misfolded proteins, activating signaling pathways, and protein translation are restored by UPR. Some diseases are caused by the overactivation of UPR and inhibition can use as a treatment for those diseases.

Frequently Asked Questions

Question 1: Tell us about the proteins made in ER.

Answer:

In lipid or protein biosynthesis, ER has a very important role. All the transmembrane proteins and lipids are produced at the membrane of ER. Proteins for all organelles are produced here including Endosome, secretory vesicles, lysosomes, Golgi apparatus, and plasma membrane.

Question 2: Explain the need for ER in cells.

Answer:

Normally it can be of both types i.e., RER and SER. The main function of this organelle is the production of proteins. Ribosomes are present on the surface of the rough endoplasmic reticulum which it got its name and because of ribosomes, they have a rough surface. These ribosomes are present to synthesize proteins.

Question 3: What qualities make ER an important organelle in a cell?

Answer:

The most important and best organelle in a cell is ER. It has ribosomes due to which proteins are formed and without proteins, cells won’t able to work. Without this organelle, the cell will be of no use as it provides the main product to the cell. SER also plays a very important role in a cell in the synthesis of different products that are essential for the cell to work properly.

Question 4: What is the membranous structure of ER?

Answer:

As if it has a single layer but it is arranged in such a way that it appears to be a double-layered organelle. Its cell membrane is the continuity of the membrane of the nucleus and there are ramps in the cell membrane of ER which looks like multistory car parking. Ribosomes are present on the outer surface giving a rough appearance in RER whereas in SER ribosomes are not present.

Question 5: What’s the way for the proteins to enter the endoplasmic reticulum?

Answer:

Those proteins which have a signal peptide of amino acid sequence can enter the endoplasmic reticulum during translation. In the endomembrane system, the proteins are bounded to organelles. Many different enzymes and complexes take place in the entry of protein in ER. Once the entry is done then that protein is processed and then it is packed and transported to its final destinations.