1. ENDOPLASMIC
RETICULUM
Dr. Amita k. Mevada
Physiology Department,
B.J.Medical college.
2. HISTORY
Inthe year 1945 The lace like membranes of
the endoplasmic reticulum were first seen in the
cytoplasm of chick embryo cells a team of
biologists, Keith R. Porter, Albert Claude, and
Ernest F. Fullam.
1952- ER term used by porter and kallman in
their published article.
3. STRUCTURE
Endoplasmic means "within the plasm" and
reticulum means "network".
A network of tubular and flat vesicular
structures in the cytoplasm is the endoplasmic
reticulum.
The tubules and vesicles interconnect with
one another.
It is a internal delivery system of cell.
It makes up approximately 12% of cell volume.
4. Endoplasmic matrix: The space inside the tubules
and vesicles is filled with a watery medium that is
different from the fluid in the cytosol outside the
endoplasmic reticulum.
Theirwalls are constructed of lipid bilayer
membranes that contain large amounts of proteins,
similar to the cell membrane.
5. Electron micrographs show that the space inside
the endoplasmic reticulum is connected with the
space between the two membrane surfaces of the
nuclear membrane (perinuclear space).
Also it is connected with golgi appratus and cell
membrane.
6. All eukaryotic cells have an ER, more than half
the total membrane except the red blood cells of
mammals.
The total surface area of this structure in some
cells-the liver cells, for instance-can be as much as
30 to 40 times the cell membrane area.
The functions of the endoplasmic reticulum vary
greatly depending on its cell type, cell function, and
cell needs.
The ER can even modify to change over time in
response to cell needs.
7. TYPES
Morphologically, two
types of endoplasmic
reticulum can be
identified
1) Rough ( granular)
endoplasmic
reticulum
2) Smooth ( agranular)
endoplasmic
reticulum
8. The quantity of RER and SER in a cell can
slowly interchange from one type to the other,
depending on changing metabolic needs.
Transformation can include embedment of new
proteins in membrane as well as structural
changes.
Sometimes, massive changes may occur in
protein content without noticeable structural
changes.
9. ROUGH ( GRANULAR) ENDOPLASMIC
RETICULUM
Ribosome: large numbers of minute granular particles
attached to the outer surfaces of many parts of the
endoplasmic reticulum.
Rough ER is well developed in cells active in protein
synthesis.eg. Russell’s bodies of plasma,
nissel’s granules of nerve cell,
acinar cell of pancreas.
White blood cells that produce infection fighting
immune system proteins called antibodies have highly
developed RER.
10. RIBOSOMES
The ribosomes in eukaryotes measure
approximately 22 x 32 nm.
Each is made up of a large and a small subunit
called, the 60S and 40S subunits, on the basis
of their rates of sedimentation in the
ultracentrifuge
The ribosomes are complex structures,
containing many different proteins and at least
three ribosomal RNAs.
They are the sites of protein synthesis.
11. These proteins typically have a hydrophobic
signal peptide at one end.
The binding site of the Ribosome on RER is
the translocon formed by the heterotrimeric
Sec61 complex.
Free ribosomes are also found in the
cytoplasm.
12. The free ribosomes synthesize cytoplasmic proteins
such as hemoglobin and the proteins found in
peroxisomes and mitochondria.
The ribosomes that become attached to the
endoplasmic reticulum synthesize all
transmembrane proteins, most secreted proteins,
and most proteins that are stored in the Golgi
apparatus, lysosomes, and endosomes.
The ribosomes bound to the RER at any one time
are not a stable part of this organelle's structure as
ribosomes are constantly being bound and released
from the membrane.
13. SMOOTH ( AGRANULAR) ENDOPLASMIC
RETICULUM
Part of the endoplasmic reticulum has no
attached ribosomes. This part is called the
agranular, or smooth, endoplasmic reticulum.
The SER consists of tubules that are located
near the cell periphery.
These tubes sometimes branch forming a
network that is reticular in appearance.
14. The network of SER allows increased surface
area for the action or storage of key enzymes
and the products of these enzymes.
The agranular endoplasmic reticulum is the site
of lipid synthesis (including oils, phospholipids
and steroids), metabolizing of carbohydrates,
regulation of calcium concentration and
detoxification of drugs and poisons.
15. Itis found in abundance with Leydig cell and
cells of adrenal cortex.
Smooth ER found in smooth and striated
muscle.
In brain cells it synthesizes male and female
hormones.
16. SARCOPLASMIC RETICULUM
The sarcoplasmic reticulum (SR), from the
Greek sarx, ("flesh“)
In skeletal and cardiac muscle, smooth ER
is modified to form sarcoplasmic reticulum.
17. The only structural difference between this
organelle and the smooth ER 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 ER synthesizes
molecules, while the SR stores and pumps
calcium ions.
19. FUNCTION OF RER
1. Insertion of proteins into the endoplasmic
reticulum membrane:
Insertion of proteins into the endoplasmic reticulum
membrane requires the correct topogenic signal
sequences in the protein.
2. Lysosomal enzymes with a mannose-6-phosphate
marker added in the Cis-Golgi network.
20. 3. 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.
4. N-linked glycosylation :
If the protein is properly folded, glycosyltransferase
recognizes the AA sequence and adds a 14-sugar
backbone to the side-chain nitrogen of Asparagine
residues(2-N-acetylglucosamine, 9-branching
mannose, and 3-glucose at the end).
21. 5. Disulfide bond formation and rearrangement:
The granular endoplasmic reticulum is also
concerned with the initial folding of polypeptide
chains with the formation of disulfide bonds by
Protein disulfide isomerases(PDI).
It confer structural stability to the tertiary and
quaternary structure of many proteins to
withstand adverse conditions such as extremes
of pH and degradative enzymes.
22. FUNCTION OF SER
1. The smooth endoplasmic reticulum (SER) has functions
in several metabolic processes, including-
-synthesis of lipids and steroids,
-metabolism of carbohydrates,
-attachment of receptors on cell membrane
proteins, and steroid metabolism.
2. Drug metabolism: The smooth ER is the site at which
some drugs are modified by microsomal enzymes, which
include the cytochrome P450 enzymes.
3. The Smooth ER also contains the enzyme glucose-6-
phosphatase, which converts glucose-6-phosphate to
glucose, a step in gluconeogenesis.
23. 4. Calcium storage
In particular, the endoplasmic or sarcoplasmic
reticulum serves as a major reservoir for calcium
ions and can sequester Ca2+ ions and allow for their
release as intracellular signaling molecules in the
cytosol. Thus, solely regulate calcium levels.
It plays a major role in excitation-contraction
coupling.
24. PROTEIN SYNTHESIS, MODIFICATION AND
INTRACELLULAR TRANSPORT
Proteins Are Formed by the Granular Endoplasmic
Reticulum:
Most synthesis begins in the endoplasmic
reticulum.
The specific products that are synthesized in
specific portions of the endoplasmic reticulum and
the Golgi apparatus.
25. The pores in the nuclear membrane allow
ribosomal subunits and mRNA transcribed off
genes in the DNA to leave the nucleus, enter the
cytoplasm, and participate in protein synthesis.
The polypeptide chains that form these proteins are
extruded into the endoplasmic reticulum.
A ribosome binds to the ER only when it begins to
synthesize a protein destined for the secretory
pathway.
26. RIBOSOME IN THE CYTOSOL BEGINS SYNTHESIZING A PROTEIN UNTIL A SIGNAL
RECOGNITION PARTICLE RECOGNIZES THE SIGNAL PEPTIDE OF 5-30 HYDROPHOBIC
AMINO ACIDS.
27. THIS SIGNAL SEQUENCE ALLOWS THE RECOGNITION PARTICLE TO BIND TO THE
RIBOSOME, CAUSING THE RIBOSOME TO BIND TO THE RER AND PASS THE NEW
PROTEIN THROUGH THE ER MEMBRANE.
28. N-GLYCANS ARE ADDED BY OLIGO-SACCHARYLTRANSFERASES ANDTHE SIGNAL
SEQUENCE IS CLEAVED BY SIGNALPEPTIDASES WITHIN THE LUMEN OF THE ER.
29. RIBOSOMES AT THIS POINT MAY BE RELEASED BACK INTO THE CYTOSOL, HOWEVER
NON-TRANSLATING RIBOSOMES ARE ALSO KNOWN TO STAY ASSOCIATED WITH
TRANSLOCONS.
30. PROTEIN TRANSPORT
As substances are formed in the endoplasmic
reticulum, especially the proteins, they are
transported through the tubules toward portions of
the smooth endoplasmic reticulum that lie nearest
the Golgi apparatus.
At this point, small transport vesicles composed of
small envelopes of smooth endoplasmic reticulum
continually break away and diffuse to the deepest
layer of the Golgi apparatus.
Inside these vesicles are the synthesized proteins
and other products from the endoplasmic reticulum.
31. Transport Vesicles:
They are surrounded by coating proteins
called COPI and COPII.
o COP II targets vesicles to the golgi and
o COP I marks them to be brought back
to the RER.
The coat protein shapes the membrane into
a bud and after budding, the protein coat is
lost.
33. Integral membrane proteins:
1) Rab proteins are key in targeting the membrane;
2) SNAP(synaptosome-associated protein) and
SNARE(Soluble N-ethylmaleimide-sensitive factor
activating protein receptor) proteins are key in the
fusion event.
vesicle-snare (v-snare) is incorporated into the vesicle
membrane, and the target-snare (t-snare) is
incorporated into the target membrane.
Docking occurs by interaction of the v-snare and t-
snare proteins.
34. Once the vesicle and the target membranes
are docked, formed 'fusion complex' must
precede the fusion of the vesicle with the
target membrane.
The interaction of the SNARE proteins and the
subsequent membrane fusion events are
typically regulated by several different cellular
proteins, including small GTPases of the Rab
class.
vesicles also contain TOR (target of
Individual
rapamycin )attachment receptor.
35.
36. PROCESSING OF ENDOPLASMIC SECRETIONS BY
THE GOLGI APPARATUS
The Golgi apparatus is a polarized structure, with cis and
trans sides.
Membranous vesicles containing newly synthesized
proteins bud off from the granular endoplasmic reticulum
and fuse with the cistern on the cis side of the apparatus.
The proteins are then passed via other vesicles to the
middle cisterns and finally to the cistern on the trans side,
from which vesicles branch off into the cytoplasm.
37. As the secretions pass toward the outermost layers
of the Golgi apparatus, it compact the endoplasmic
reticular secretions into highly concentrated packets.
Finally, both small and large vesicles continually
break away from the Golgi apparatus, carrying with
them the compacted secretory substances, and in
turn, the vesicles diffuse throughout the cell.
38. SECRETORY VESICLES
Almost all such secretory substances are formed by
the endoplasmic reticulum-Golgi apparatus system
and are then released from the Golgi apparatus into
the cytoplasm in the form of storage vesicles called
secretory vesicles or secretory granules.
From the trans Golgi, secretory vesicles shuttle to
the lysosomes and to the cell exterior via
constitutive and nonconstitutive pathways, both
involving exocytosis.
Conversely, vesicles are pinched off from the cell
membrane by endocytosis and pass to
endosomes. From there, they are recycled.
39. VESICULAR TRAFFICKING
• Pathways:
• Endocytic illustrated in
green arrows
• Biosynthetic-secretory
illustrated with red
arrows
• Retrieval illustrated
with blue arrows
40.
41. When a glandular cell is bathed in radioactive
amino acids, newly formed radioactive protein
molecules can be detected in the granular
endoplasmic reticulum within 3 to 5 minutes.
Within 20 minutes, newly formed proteins are
already present in the Golgi apparatus, and within 1
to 2 hours, radioactive proteins are secreted from
the surface of the cell.
42. SYNTHESIS OF LIPIDS BY THE SMOOTH
ENDOPLASMIC RETICULUM
The SER synthesizes lipids, especially phospholipids
and cholesterol.
These are rapidly incorporated into the lipid bilayer of the
endoplasmic reticulum itself, thus causing the
endoplasmic reticulum to grow more extensive.
To keep the endoplasmic reticulum from growing beyond
the needs of the cell, small vesicles called ER vesicles
or transport vesicles continually break away from the
smooth reticulum and then migrate rapidly to the Golgi
apparatus.
43. PROTEIN FOLDING AND QUALITY CONTROL
IN THE ENDOPLASMIC RETICULUM
Protein folding is the physical process by which a
polypeptide folds into its characteristic and
functional three-dimensional structure from random
coil.
Each protein exists as an unfolded polypeptide or
random coil when translated from a sequence of
mRNA to a linear chain of amino acids.
This polypeptide lacks any developed three-
dimensional structure (the left hand side of the
neighboring figure).
44. Amino acids interact with each other to produce a
well-defined three-dimensional structure, the folded
protein (the right hand side of the figure), known as
the native state.
The correct three-dimensional structure is essential
to function, although some parts of functional
proteins may remain unfolded.
Only correctly folded proteins can move on along
the secretory pathway.
45. The most important of protein folding steps are N-
linked glycosylation and disulfide bond formation.
1) N-linked glycosylation occurs as soon as the
protein sequence passes into the ER through the
translocon, where it is glycosylated with a sugar
molecule that forms the key ligand for the lectin
molecules calreticulin (CRT) and calnexin (CNX).
2) Protein disulfide confer structural stability to the
protein.
46. Protein folding steps involve a range of
folding enzymes and molecular chaperones
to coordinate and regulate reactions, in
addition to a range of substrates required
for the reactions to take place.
47. MOLECULAR CHAPERONES
ER resident folding assistants which associate with
the unfolded or misfolded substrates, preventing
their aggregation and thus aiding them to achieve
their native conformation.
As long as folding is incomplete and the proteins
are bound to chaperones, they are retained in the
ER.
They are expressed constitutively, but are induced
by stress conditions like heat shock or glucose
starvation; hence the synonyms heat shock
proteins (HSPs) or glucose-regulated proteins
(GRPs).
48. Family Protein Function
Hsp40 ERdj1/Mtj1 Cofactors for Hsp70
ERdj2/hSec63
ERdj3/HEDJ/ERj3/ABBP-2
ERdj4/Mdj1
ERdj5/JPD1
Hsp60 None
Hsp70 GRP78/BiP Conventional chaperone
Hsp90 GRP94/endoplasmin/ERp99 Conventional chaperone
Hsp100 Torsin A? ?
GrpE-like BAP/Sil1 Cofactors for Hsp70
GRP170
Lectins Calnexin Glycoprotein-dedicated
chaperones
Calreticulin
EDEM1, EDEM2, EDEM3
49. FOLDING ENZYMES
Protein
disulfide isomerase(PDI), ERp72,
ERp61, GRP58/Erp57, ERp44, ERp29 and
PDI-P5.
Functions: oxidize cystein residues and catalyze
formation of covalent bonds between cysteine
residues of a polypeptide.
Peptidyl-prolyl
cis-trans isomerases (PPI)
catalyze isomerization of peptidyl-prolyl
bonds.
50. Successful protein folding requires a tightly
controlled environment of substrates that include-
1. Glucose to meet the metabolic energy
requirements of the functioning molecular
chaperones;
2. Calcium that is stored bound to resident
molecular chaperones and;
3. Redox buffers that maintain the oxidising
environment required for disulfide bond
formation.
51. UNFOLDED PROTEIN RESPONSE (UPR)
Thecellular stress response activated in
response to an accumulation of unfolded
or misfolded proteins in the lumen of the
endoplasmic reticulum.
52. The UPR has two primary aims:
1. Initially to restore normal function of the cell
by halting protein translation
2. Activate the signaling pathways that lead to
increasing the production of molecular
chaperones involved in protein folding.
If these objectives are not achieved within a
certain time lapse or the disruption is
prolonged, the UPR aims towards apoptosis.
53. The sugar molecule remains the means by which
the cell monitors protein folding & recognising
malfolding proteins, as the malfolding protein
becomes characteristically devoid of glucose
residues.
The lectin-type chaperones- calnexin/calreticulin
(CNX/CRT) provide immature glycoproteins the
opportunity to reach their native conformation by
way of reglucosylating these glycoproteins by an
enzyme called UDP-glucose-glycoprotein
glucosyltransferase( UGGT).
54. Ifthis fails to restore the normal folding
process, exposed hydrophobic residues of the
malfolded protein are bound by the protein
glucose regulate protein 78 (Grp78/ BiP), binds
to the hydrophobic regions of unfolded proteins
via a substrate-binding domain that prevents
the unfolded protein from further transit and
secretion.
Then it facilitates folding through
conformational change evoked by the
hydrolysis of ATP by ATPase domain.
56. Where circumstances continue to cause a
particular protein to malfold, the protein is
recognised as posing a threat to the proper
functioning of the ER, as they can
aggregate to one another and accumulate.
In such circumstances, the protein is guided
through endoplasmic reticulum-associated
degradation (ERAD).
58. 1) RECOGNITION OF MISFOLDED OR MUTATED PROTEINS
IN THE ENDOPLASMIC RETICULUM
The recognition of misfolded or mutated proteins
depends on the detection of substructures within
proteins such as exposed hydrophobic regions,
unpaired cysteine residues and immature
glycans.
Calnexin/calreticulin (CNX/CRT) reglucosylating
these glycoproteins by an enzyme, UGGT.
59. Terminally misfolded proteins must be extracted
from CNX/CRT by ER mannosidase I and
EDEM (ER degradation-enhancing alpha-
mannosidase-like protein).
ER mannosidase removes one mannose
residue from the glycoprotein which is
recognized by EDEM(1,2,3) and target for
degradation.
60. 2) RETRO-TRANSLOCATION INTO THE CYTOSOL
Terminally misfolded proteins transported from
the endoplasmic reticulum back into cytoplasm
by the protein complex Sec61 .
Ubiquitin-binding factors- valosine-containing
protein (VCP/p97) transports substrates from
the endoplasmic reticulum to the cytoplasm
with its ATPase activity
61. CHECKPOINTS
1. ERAD-C Monitors the folding state of the cytosolic
domains of membrane proteins..
2. ERAD-L where the luminal domains are monitored.
membrane proteins surviving the first checkpoint,
soluble proteins (entirely luminal and thus bypass the
first checkpoint )
3. ERAD-M inspection of transmembrane domains of
proteins.
62. 3) The ubiquitin-proteasome pathway
1. ubiquitin-activating enzyme E1 hydrolyses ATP and forms a high-energy
thioester linkage between a cysteine residue in its active site and the C-
terminus of ubiquitin.
Biochemical Journal (2004) 379, 513-525 -
63. The ubiquitin-proteasome pathway
2. The resulting activated ubiquitin is then passed to E2, which is a
ubiquitin-conjugating enzyme.
Biochemical Journal (2004) 379, 513-525 -
64. The ubiquitin-proteasome pathway
3. More specifically ubiquitin protein ligases called E3, bind to the misfolded
protein and then align the protein and E2, thus facilitating the attachment of
ubiquitin to lysine residues of the misfolded protein
Biochemical Journal (2004) 379, 513-525 -
65. The ubiquitin-proteasome pathway
Following successive addition of ubiquitin molecules to lysine residues of
the previously attached ubiquitin, a polyubiquitin chain is formed.
Biochemical Journal (2004) 379, 513-525 -
67. ENDOPLASMIC RETICULUM STRESS
When cells synthesize secretory proteins in
amounts that exceed the capacity of the
folding apparatus and ERAD machinery,
leading to the accumulation of unfolded/
misfolded proteins which can threaten the
cell.
68. Unfolded proteins exposed hydrophobic amino-
acid residues and tend to form protein
aggregates evokes ER stress.
Disturbances in redox regulation, calcium
regulation, glucose deprivation, and viral
infection can lead to ER stress.
This ER stress is emerging as a potential cause
of damage in hypoxia/ischemia, insulin
resistance and other disorders.
69. ER STRESS- INDUCING CHEMICALS
First group: glycosylation inhibitor
Tunicamycin
2-Deoxy-D-glucose is less efficient than
tunicamycin.
70. Second group: Ca2+ metablism disruptor
Ca2+ ionophore (A23187)
Ca2+ pump inhibitor (thapsigargin) inhibition of the
Sarco/ Endoplasmic Reticulum Ca2+-ATPase
(SERCA) leads to ER Ca+2 depletion.
71. The third group: reducing agents
Dithiothreitol(DTT)-Reduce the disulfide bridges of
proteins.
β-mecaptoethanol
fenretinide and bortezomib (Velcade) induce ER
stress leading to apoptosis in melanoma cells.
The fourth group: hypoxia
72. RESPONSE PATHWAYS FOR ER
STRESS
The mammalian ER stress response has four
mechanisms:
(1) translational attenuation of unfolded proteins
(2) enhanced expression of ER chaperones and
(3) The transcriptional induction of ERAD component
genes to increase ERAD capacity
(4) induction of apoptosis to safely dispose of cells
injured by ER stress to ensure the survival of the
organism..
73.
74. ENDOPLASMIC RETICULUM STORAGE
DISEASES
Endoplasmic reticulum (ER) storage
diseases (ERSDs) are caused by the
intracellular accumulation of endogenous
compounds which directly or indirectly
impair cellular functions and may even lead
to cell death.
75. To exit the ER and be transported to their site of
activity, newly synthesized proteins must pass a
tightly controlled quality control test and some
proteins must expose cytosolic and luminal signals
for forward transport.
Proteins that fail to do so are rerouted to the cytosol
for ERAD.
Unbalances in mechanisms that coordinate protein
synthesis, folding, transport and degradation
processes are at the basis of many human
diseases.
76. DISEASES CAUSED BY PROTEIN MISFOLDING RESULTING
IN DISPOSAL (LOSS OF FUNCTION)
Conformational disorders are often familial
because mutations in the polypeptide
sequences may strongly affect the folding
efficiency.
They may lead to loss-of-function conditions, in
which a membrane or secreted protein is
retained and subsequently degraded.
77. DISEASES CAUSED BY PROTEIN MISFOLDING RESULTING IN
DISPOSAL (LOSS OF FUNCTION)
Protein Disease
α1-Antitrypsin Hereditary lung emphysema
α-d-Galactosidase Fabry disease
ABCA1 transporter Tangier disease
β-Glucocerebrosidase Gaucher disease
β-Hexoseaminidase Tay-Sachs disease
β-Secretase (splice variants) Alzheimer's disease
Capillary morphogenesis factor-2 Infantile systemic hyalinosis
CD4 HIV1 infection
Class 1 MHC heavy chain Infantile CMV-linked hepatitis
CLD anion transporter Congenital chloride diarrhea
Complement C1 inhibitor Hereditary angioedema
Cystic fibrosis transmembrane regulator Cystic fibrosis, recurrent nasal polyps, congenital
bilateral absence of vas deferens, idiopathic
pancreatitis
78. DISEASES CAUSED BY PROTEIN MISFOLDING RESULTING IN
DISPOSAL (LOSS OF FUNCTION)
Protein Disease
DTDST anion transporter Diastrophic displasia
Gonadotropin-releasing hormone receptor Hypogonadotropic hypogonadism
Growth hormone receptor Laron syndrome
HFE Autosomal recessive hereditary hemochromatosis
Insulin receptor Diabetes mellitus, insulin-resistant syndrome
Low-density lipoprotein receptor Familial hypercholesterolemia
Myeloperoxidase Myeloperoxidase deficiency
Pendrin Pendred syndrome
Polycystin-2 Polycystic kidney disease 2
Protein C Venous thromboembolism
Tyrosinase Oculocutaneous albinism, amelanotic melanoma
von Willebrand factor Bleeding disorders
Voltage-gated potassium channel Congenital long QT syndrome
21-Hydroxylase Congenital adrenal hyperplasia
79. DISEASES CAUSED BY PROTEIN MISFOLDING CAUSING
RETENTION/DEPOSITION
(GAIN OF TOXIC FUNCTION AND/OR LOSS OF FUNCTION)
Ifdisposal is not efficient, aberrant proteins
accumulate in or outside cells and may initiate
unfolded protein responses eventually leading to
cell death and triggering severe damages to tissues
and organs.
80. An interesting case is the pathology caused by α1-
antitrypsin mutation.
α1-Antitrypsin is the principal blood-borne inhibitor
of the destructive neutrophil elastase in the lungs.
Mutated α1-antitrypsin is not secreted from liver
cells and actually accumulates forming intracellular
deposits.
The loss-of-function phenotype observed at the
level of patient's lungs (emphysema) is therefore
accompanied by a gain-of-toxic-function phenotype
at the level of the liver (liver cirrhosis)
81. DISEASES CAUSED BY PROTEIN MISFOLDING CAUSING
RETENTION/DEPOSITION (GAIN OF TOXIC FUNCTION AND/OR LOSS OF
FUNCTION)
Protein Disease
α1-Antitrypsin Liver failure, cirrhosis
α-Synuclein Parkinson's disease
Aquaporin-2 Autosomal nephrogenic diabetes insipidus
Arginine vasopressin Familial neurohypophysial diabetes insipidus
Collagen type I–IV Osteogenesis imperfecta, Ehlers-Danlos syndrome,
idiopathic osteoporosis, Caffey disease
Connexin Charcot-Marie-Tooth syndrome
Copper transporter Menkes disease
Fibrillin-1 Marfan syndrome
Fibrinogen Liver failure
Granulocyte colony-stimulating factor Severe congenital neutropenia
HERG potassium channel Hereditary long QT syndrome
HMG-CoA reductase Heart failure
Immunoglobulin chains Heavy chain disease
Lipoprotein lipase Familial chylomicronemia
82. DISEASES CAUSED BY PROTEIN MISFOLDING CAUSING
RETENTION/DEPOSITION (GAIN OF TOXIC FUNCTION AND/OR LOSS OF
FUNCTION)
Protein Disease
Peripheral myelin protein 22 Pael receptor
Prepro-vasopressin Neuroligin-3
Proteolipid protein Parathyroid hormone-related peptide
RET protooncogene Hirschsprung disease, central
hypoventilation syndrome
Rhodopsin Autosomal dominant retinitis
pigmentosa
Sedlin Spondylo-epiphyseal displasia tarda
Several (presenilin, hungtingtin, PrP,…) Neurodegenerative diseases
(Alzheimer's, Parkinson's, Huntington's,
Creuzfeld-Jakob)
TorsinA Dystonia, myoclonic-dystonia syndrome
Thyroglobulin Congenital hypothyroid goiter
Wilson disease protein Wilson disease
83. DISEASES CAUSED BY MUTATION/OVEREXPRESSION OF
ER/CYTOSOLIC FACTORS INVOLVED IN
BIOGENESIS/DEGRADATION OF PROTEINS EXPRESSED IN
THE ER
Diseases can also be caused by defects in
the cellular machinery that aids in protein
biosynthesis or that regulates disposal of
folding defective polypeptides.
84. Example:
ERGIC53 is a carbohydrate-binding sorting
receptor. that cycles between the ER and ER-Golgi-
intermediate compartment (ERGIC).
It packages properly folded proteins into COPII
vesicles for anterograde trafficking out of the ER by
binding to their high-mannose side chains.
Mutations in ERGIC53 disrupt the trafficking out of
the ER of the blood coagulation factors V and VIII,
thereby causing bleeding disorders
85. DISEASES CAUSED BY MUTATION/OVEREXPRESSION OF ER/CYTOSOLIC
FACTORS INVOLVED IN BIOGENESIS/DEGRADATION OF PROTEINS EXPRESSED
IN THE ER
Protein Disease
Combined factors V/VIII deficiency, bleeding
ERGIC53
disorder
Glucosidase I Hypotonia and dysmorphism
Glucosidase II, β-subunit/hepatocystin Polycystic liver disease
Inclusion body myopathy, Paget's disease of
p97/Cdc48/VCP
the bone, and frontotemporal dementia
Sec62 Prostate and colorectal cancer
Sec63 Polycystic liver disease, small bowel cancer
Sil1/BAP Marinesco-Sjoegren syndrome
86. PHARMACOLOGICAL AND CHEMICAL CHAPERONES
TO RESCUE STRUCTURALLY DEFECTIVE,
FUNCTIONAL PROTEINS
Promote and/or accelerate productive folding and
inhibit ER retention, thus facilitating the transport of
the polypeptide to its site of action.
Example4-phenyl butyrate (PBA), glycerol,
trimethylamine N-oxide,dimethyl sulfoxide,
deuterated water and derivatives of bile acids such
as ursodeoxycholic acid.
Require high dosageslimited therapeutic value.
One chemical chaperone, PBA, that has been
approved by the United States Food and Drug
Administration for clinical use for type 2 diabetes
mellitus or for α1-antitrypsin deficiency.
