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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 In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, ...
made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most
eukaryotic cells Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryotic cells
and forms an interconnected network of flattened, membrane-enclosed sacs known as
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle of the endoplasmic reticulum and Golgi apparatus. A Golgi stack may contain anywhere from three to twenty cisternae, but most contain about six cisternae. Golgi cisternae can be sepa ...

cisterna
e (in the RER), and tubular structures in the SER. The membranes of the ER are continuous with the outer
nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a c ...

nuclear membrane
. The endoplasmic reticulum is not found in
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...

red blood cell
s, or
spermatozoa A spermatozoon (pronounced , alternate spelling spermatozoön; plural spermatozoa; from grc, σπέρμα ("seed") and grc, ζῷον ("living being")) is a motile Motility is the ability of an organism In biology, an organism (from An ...

spermatozoa
. The two types of ER share many of the same
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s and engage in certain common activities such as the synthesis of certain
lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanis ...
s and
cholesterol Cholesterol is any of a class of certain organic compound, organic molecules. A cholesterol is a sterol (or chemical modification, modified steroid), a type of lipid. Cholesterol is biosynthesis, biosynthesized by all animal Cell (biology)#Euk ...

cholesterol
. Different types of
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a small room, hut, or cave in which a monk or religious recluse lives * Prison cell, a room used to hold peopl ...
contain different ratios of the two types of ER depending on the activities of the cell. Rough endoplasmic reticulum(RER) found mainly toward the nucleus of cell and smooth endoplasmic reticulum(SER) found towards the cell membrane or plasma membrane of cell. The outer (
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a s ...
ic) face of the rough endoplasmic reticulum is studded with
ribosome Ribosomes ( ), also called Palade granules, are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids ...

ribosome
s that are the sites of
protein synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...

protein synthesis
. The rough endoplasmic reticulum is especially prominent in cells such as
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein biosynthesis, Protein synthesis * Storage protein, Protein storage * Transformation of carbohyd ...
s. The smooth endoplasmic reticulum lacks ribosomes and functions in
lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanis ...
synthesis but not
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities A bubble of exhaled gas in water In common usage and classical mechanics, a phys ...

metabolism
, the production of
steroid hormone A steroid hormone is a steroid A steroid is a biologically active organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds ...
s, and
detoxification Detoxification or detoxication (detox for short) is the physiological or medicinal removal of toxic Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism In biology, an orga ...
. The smooth endoplasmic reticulum is especially abundant in mammalian
liver The liver is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's t ...

liver
and
gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes (sex cells) and sex hormones of an organism. In the female of the species the reproductive cells are the egg cells, and in the male the reproductive cells are t ...
cells. The ER was observed with
light microscope The optical microscope, also referred to as a light microscope, is a type of microscope that commonly uses visible spectrum, visible light and a system of lens (optics), lenses to generate magnified images of small objects. Optical microscopes ...
by Garnier in 1897, who coined the term ''ergastoplasm''. With
electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hig ...

electron microscopy
, the lacy membranes of the endoplasmic reticulum were first seen in 1945 by Keith R. Porter,
Albert Claude Albert Claude (24 August 1899 – 22 May 1983) was a Belgian Belgian may refer to: * Something of, or related to, Belgium Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Western Europe ...
, and Ernest F. Fullam. Later, the word ''
reticulum Reticulum is a small, faint constellation in the southern sky. Its name is Latin for a small net (device), net, or reticle—a net of crosshairs at the focus of a telescope eyepiece that is used to measure star positions. The constellation is be ...

reticulum
'', which means "network", was applied by Porter in 1953 to describe this fabric of membranes.


Structure

The general structure of the endoplasmic reticulum is a network of membranes called
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle of the endoplasmic reticulum and Golgi apparatus. A Golgi stack may contain anywhere from three to twenty cisternae, but most contain about six cisternae. Golgi cisternae can be sepa ...

cisterna
e. These sac-like structures are held together by the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

cytoskeleton
. The
phospholipid membrane The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electrical charge on one side and a negative charge on another side, which produces the resting pot ...
encloses the cisternal space (or lumen), which is continuous with the
perinuclear space The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive elect ...
but separate from the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a s ...
. 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.


Rough endoplasmic reticulum

The surface of the rough endoplasmic reticulum (often abbreviated ''RER'' or ''rough ER''; also called ''granular endoplasmic reticulum'') is studded with protein-manufacturing
ribosome Ribosomes ( ), also called Palade granules, are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids ...

ribosome
s giving it a "rough" appearance (hence its name). The binding site of the ribosome on the rough endoplasmic reticulum is the
translocon The translocon (also known as a translocator or translocation channel) is a complex of protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , ...
. 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
translating
the
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA i ...

mRNA
of a protein destined for the
secretory pathway Secretion is the movement of material from one point to another, such as a secreted chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass and takes up sp ...
. The first 5–30
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s polymerized encode a
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acid Amino acids are organic ...
, a molecular message that is recognized and bound by a
signal recognition particle The signal recognition particle (SRP) is an abundant, cytosolic, universally conserved ribonucleoprotein (protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (bioch ...
(SRP). Translation pauses and the ribosome complex binds to the RER
translocon The translocon (also known as a translocator or translocation channel) is a complex of protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , ...
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 A protease (also called a peptidase or proteinase) is an enzyme that catalysis, catalyzes (increases the rate of) proteolysis, the breakdown of proteins into smaller polypeptides or single amino acids. They do this by cleaving the peptide bonds wit ...
), 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. The membrane of the rough endoplasmic reticulum forms large double-membrane sheets that are located near, and continuous with, the outer layer of the
nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electr ...

nuclear envelope
. 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
multi-story car park A multistorey car park (British English, British and Singapore English, Singapore English language, English) or parking garage (American English), also called a multistory, parkade (mainly Canadian English, Canadian), parking structure, parking ...
. Although there is no continuous membrane between the endoplasmic reticulum and the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that stu ...

Golgi apparatus
, membrane-bound transport vesicles shuttle proteins between these two compartments. Vesicles are surrounded by coating proteins called COPI and COPII.
COPII COPII is a coatomer The coatomer is a protein complex that coats membrane-bound vesicle (biology)#Transport vesicles, transport vesicles. Two types of coatomers are known: *COPI (retrograde transport from Golgi apparatus, trans-Golgi network to ...
targets vesicles to the Golgi apparatus and
COPI Raúl Damonte Botana (November 20, 1939, Buenos Aires Buenos Aires ( or ; ), officially Autonomous City of Buenos Aires, is the capital Capital most commonly refers to: * Capital letter Letter case (or just case) is the distinction b ...

COPI
marks them to be brought back to the rough endoplasmic reticulum. The rough endoplasmic reticulum works in concert with the
Golgi complex The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that stu ...
to target new proteins to their proper destinations. The second method of transport out of the endoplasmic reticulum involves areas called
membrane contact site Membrane contact sites (MCS) are close appositions between two organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, includ ...
s, where the membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer of lipids and other small molecules. The rough endoplasmic reticulum is key in multiple functions: * Manufacture of
lysosomal
lysosomal
enzymes with a
mannose-6-phosphate Mannose-6-phosphate (M6P) is a molecule bound by lectin in the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''o ...

mannose-6-phosphate
marker added in the ''cis''-Golgi network. * Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory manner involving
clathrin Clathrin is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, f ...

clathrin
and paired basic amino acids in the
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acid Amino acids are organic ...
. *
Integral membrane proteins An integral membrane protein (IMP) is a type of 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. Int ...
that stay embedded in the membrane as vesicles exit and bind to new membranes.
Rab Rab ( dlm, Arba, la, Arba, it, Arbe, german: Arbey) is an island in Croatia , image_flag = Flag of Croatia.svg , image_coat = Coat of arms of Croatia.svg , anthem = "Lijepa naša domovino ''Lijepa n ...
proteins are key in targeting the membrane; SNAP and
SNARE Snare most often refers to: * Snare drum The snare drum or side drum is a percussion instrument that produces a sharp staccato sound when the head is struck with a drum stick, due to the use of a series of stiff wires held under tension against ...
proteins are key in the fusion event. * Initial
glycosylation Glycosylation (see also chemical glycosylationA chemical glycosylation reaction involves the coupling of a glycosyl donor, to a glycosyl acceptor forming a glycoside. If both the donor and acceptor are sugars, then the product is an oligosacchar ...

glycosylation
as assembly continues. This is N-linked (O-linking occurs in the Golgi). ** N-linked glycosylation: If the protein is properly folded,
oligosaccharyltransferase Oligosaccharyltransferase or OST () 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 ...
recognizes the AA sequence
N
N
X
S
S
or
N
N
X
T
T
(with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-''N''-acetylglucosamine, 9-branching
mannose Mannose is a sugar Sugar is the generic name for , soluble s, many of which are used in food. Simple sugars, also called s, include , , and . Compound sugars, also called s or double sugars, are molecules made of two monosaccharides joine ...

mannose
, and 3-
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
at the end) to the side-chain
nitrogen Nitrogen is the chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science ...

nitrogen
of Asn.


Smooth endoplasmic reticulum

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 that contain lipids and proteins made in the ER, detach from the ER and start moving to the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that stu ...

Golgi apparatus
. Specialized cells can have a lot of smooth endoplasmic reticulum and in these cells the smooth ER has many functions. It synthesizes
lipids In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanis ...

lipids
,
phospholipids Phospholipids, also known as phosphatides, are a class of lipids whose molecule has a hydrophile, hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glyce ...

phospholipids
, and
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes which alter membrane fluidity; and ...
. Cells which secrete these products, such as those in the
testes Testicle or testis (plural testes) is the male Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male or ...

testes
,
ovaries The ovary is an organ found in the female reproductive system 300px, 1. Labia_majora.html"_;"title="Vulva: 2. Labia_majora">Vulva: 2. Labia_majora; 3. Labia_minora; 4. Vulval_vestibule.html" "title="Labia_minora.html ...

ovaries
, and
sebaceous gland A sebaceous gland is a microscopic exocrine Exocrine glands are gland In animals, a gland is a group of cells in an animal's body that synthesizes substances (such as hormone A hormone (from the Greek participle , "setting in motion") is a ...
s have an abundance of smooth endoplasmic reticulum. 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. In muscle cells, it regulates
calcium ion Calcium is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, beha ...
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 Glucose 6-phosphatase (, G6Pase) is an enzyme that hydrolyzes glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose. Glucose is then exported from the cell via glucose transporters, glucose transporter membrane pr ...
, which converts
glucose-6-phosphate Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cell (biology), cells as the majority of glucose entering a cell will become phosphoryl ...
to glucose, a step in
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformati ...

gluconeogenesis
. It is connected to the
nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane A polarized membrane is a lipid bilayer, lipid membrane that has a positive electr ...

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. 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.


Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR), from the Greek σάρξ ''sarx'' ("flesh"), is smooth ER found in
muscle cell A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell Cardiac muscle cells or cardiomyocytes (also known as myocardiocytes or cardiac myocytes) are the muscle cells (myocyte A muscle cell is also known as a m ...
s. The only structural difference between this organelle and the smooth endoplasmic reticulum is the medley 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. 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 Muscle contraction is the activation of tension Tension may refer to: Science * Psychological stress * Tension (physics), a force related to the stretching of an object (the opposite of compression) * Tension (geology), a stress which stretches ...
.


Functions

The endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs called
cisterna A cisterna (plural cisternae) is a flattened membrane vesicle of the endoplasmic reticulum and Golgi apparatus. A Golgi stack may contain anywhere from three to twenty cisternae, but most contain about six cisternae. Golgi cisternae can be sepa ...

cisterna
e and the transport of synthesized proteins in
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features of ...
to the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that stu ...

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 Protein disulfide isomerase, or PDI, is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry) ...
(PDI), ERp29, the
Hsp70#REDIRECT Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family In human society, family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other r ...

Hsp70
family member BiP/Grp78,
calnexin Calnexin (CNX) is 67kDa integral protein (that appears variously as a 90kDa, 80kDa, or 75kDa band on western blotting depending on the source of the antibody) of the endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transp ...
,
calreticulin Calreticulin also known as calregulin, CRP55, CaBP3, calsequestrin-like protein, and endoplasmic reticulum resident protein 60 (ERp60) is a protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chai ...
, 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 The unfolded protein response (UPR) is a cellular stress responseCellular stress response is the wide range of molecular biology, molecular changes that cell (biology), cells undergo in response to environmental stressors, including extremes of te ...
as a stress response in the ER. Disturbances in
redox Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter ...

redox
regulation, calcium regulation, glucose deprivation, and viral infection or the over-expression of proteins 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.


Protein transport

Secretory proteins, mostly
glycoproteins Glycoproteins are protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including ...
, 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 Peptides (from Greek language Greek ( el, label=Modern Greek Modern Greek (, , or , ''Kiní Neoellinikí Glóssa''), generally referred to by speakers simply as Greek (, ), refers collectively to the dialects of the Greek language spoken ...
chain (i.e., a protein) contains a few
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s that work as an address tag, which are removed when the polypeptide reaches its destination. Nascent peptides reach the ER via the
translocon The translocon (also known as a translocator or translocation channel) is a complex of protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , ...
, a membrane-embedded multiprotein complex. Proteins that are destined for places outside the endoplasmic reticulum are packed into transport
vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry) In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and liv ...
s and moved along the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filament In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical proces ...

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. 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 Motif may refer to: General concepts * Motif (chess composition), an element of a move in the consideration of its purpose * Motif (folkloristics), a recurring element that creates recognizable patterns in folklore and folk-art traditions * 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 protein. 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.


Bioenergetics regulation of ER ATP supply by a CaATiER mechanism

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. The ER ATP transporter, SLC35B1/AXER, was recently cloned and characterized, and the mitochondria supply ATP to the ER through a ''Ca2+-antagonized transport into the ER'' (''CaATiER'') mechanism. 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.


Clinical significance

Increased and supraphysiological ER stress in pancreatic β cells disrupts normal insulin secretion, leading to hyperinsulinemia and consequently peripheral insulin resistance associated with obesity in humans. Abnormalities in
XBP1 X-box binding protein 1, also known as XBP1, is a protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir ...
lead to a heightened endoplasmic reticulum stress response and subsequently causes a higher susceptibility for inflammatory processes that may even contribute to
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of structure or function of neuron A neuron or nerve cell is an membrane p ...
. In the
colon Colon commonly refers to: * Colon (punctuation) (:), a punctuation mark * Major part of large intestine, the final section of the digestive system Colon may also refer to: Places * Colon, Michigan, US * Colon, Nebraska, US * Kowloon, Hong Kong, s ...

colon
, XBP1 anomalies have been linked to the inflammatory bowel diseases including
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...

Crohn's disease
. The
unfolded protein response The unfolded protein response (UPR) is a cellular stress responseCellular stress response is the wide range of molecular biology, molecular changes that cell (biology), cells undergo in response to environmental stressors, including extremes of te ...
(UPR) is a
cellular stress response Cellular stress response is the wide range of molecular biology, molecular changes that cell (biology), cells undergo in response to environmental stressors, including extremes of temperature, exposure to toxins, and mechanical damage. Cellular stre ...
related to the endoplasmic reticulum. The UPR is activated in response to an accumulation of unfolded or misfolded
protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a No ...

protein
s in the lumen of the endoplasmic reticulum. The UPR functions to restore normal function of the cell by halting protein
translation Translation is the communication of the meaning Meaning most commonly refers to: * Meaning (linguistics), meaning which is communicated through the use of language * Meaning (philosophy), definition, elements, and types of meaning discusse ...
, degrading misfolded proteins, and activating the signaling pathways that lead to increasing the production of molecular chaperones involved in
protein folding Protein folding is the physical process Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass ...

protein folding
. Sustained overactivation of the UPR has been implicated in
prion Prions are misfolded protein Protein folding is the physical process Physical changes are changes affecting the form of a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matte ...

prion
diseases as well as several other
neurodegenerative diseases A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic l ...
and the inhibition of the UPR could become a treatment for those diseases.


References


External links


Endoplasmic Reticulum

Lipid and protein composition of Endoplasmic reticulum
in OPM database
Animations of the various cell functions referenced here
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