Endoplasmic reticulum by amitaPresentation Transcript
ENDOPLASMICRETICULUM Dr. Amita k. Mevada Physiology Department, B.J.Medical college.
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.
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.
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.
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.
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.
TYPES Morphologically, two types of endoplasmic reticulum can be identified1) Rough ( granular) endoplasmic reticulum2) Smooth ( agranular) endoplasmic reticulum
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.
ROUGH ( GRANULAR) ENDOPLASMICRETICULUM 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.
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.
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.
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 organelles structure as ribosomes are constantly being bound and released from the membrane.
SMOOTH ( AGRANULAR) ENDOPLASMICRETICULUM 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.
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.
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.
SARCOPLASMIC RETICULUM The sarcoplasmic reticulum (SR), from the Greek sarx, ("flesh“) In skeletal and cardiac muscle, smooth ER is modified to form sarcoplasmic reticulum.
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.
FUNCTION OFENDOPLASMIC RETICULUM
FUNCTION OF RER1. Insertion of proteins into the endoplasmicreticulum 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.
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).
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.
FUNCTION OF SER1. 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.
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.
PROTEIN SYNTHESIS, MODIFICATION ANDINTRACELLULAR TRANSPORTProteins Are Formed by the Granular EndoplasmicReticulum: Most synthesis begins in the endoplasmic reticulum. The specific products that are synthesized in specific portions of the endoplasmic reticulum and the Golgi apparatus.
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.
RIBOSOME IN THE CYTOSOL BEGINS SYNTHESIZING A PROTEIN UNTIL A SIGNALRECOGNITION PARTICLE RECOGNIZES THE SIGNAL PEPTIDE OF 5-30 HYDROPHOBICAMINO ACIDS.
THIS SIGNAL SEQUENCE ALLOWS THE RECOGNITION PARTICLE TO BIND TO THERIBOSOME, CAUSING THE RIBOSOME TO BIND TO THE RER AND PASS THE NEWPROTEIN THROUGH THE ER MEMBRANE.
N-GLYCANS ARE ADDED BY OLIGO-SACCHARYLTRANSFERASES ANDTHE SIGNALSEQUENCE IS CLEAVED BY SIGNALPEPTIDASES WITHIN THE LUMEN OF THE ER.
RIBOSOMES AT THIS POINT MAY BE RELEASED BACK INTO THE CYTOSOL, HOWEVERNON-TRANSLATING RIBOSOMES ARE ALSO KNOWN TO STAY ASSOCIATED WITHTRANSLOCONS.
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.
Transport Vesicles: They are surrounded by coating proteins called COPI and COPII.o COP II targets vesicles to the golgi ando 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.
DIFFERENT COATS IN VESICULAR TRAFFICING
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.
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.
PROCESSING OF ENDOPLASMIC SECRETIONS BYTHE 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.
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.
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.
VESICULAR TRAFFICKING• Pathways:• Endocytic illustrated in green arrows• Biosynthetic-secretory illustrated with red arrows• Retrieval illustrated with blue arrows
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.
SYNTHESIS OF LIPIDS BY THE SMOOTHENDOPLASMIC 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.
PROTEIN FOLDING AND QUALITY CONTROLIN 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).
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.
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.
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.
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).
Family Protein FunctionHsp40 ERdj1/Mtj1 Cofactors for Hsp70 ERdj2/hSec63 ERdj3/HEDJ/ERj3/ABBP-2 ERdj4/Mdj1 ERdj5/JPD1Hsp60 NoneHsp70 GRP78/BiP Conventional chaperoneHsp90 GRP94/endoplasmin/ERp99 Conventional chaperoneHsp100 Torsin A? ?GrpE-like BAP/Sil1 Cofactors for Hsp70 GRP170Lectins Calnexin Glycoprotein-dedicated chaperones Calreticulin EDEM1, EDEM2, EDEM3
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.
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.
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.
The UPR has two primary aims:1. Initially to restore normal function of the cell by halting protein translation2. 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.
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).
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.
UNFOLDED PROTEIN RESPONSE
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).
ENDOPLASMIC-RETICULUM-ASSOCIATEDPROTEIN DEGRADATION(ERAD) The process of ERAD can be divided into four step:1. Recognition,2. Retrotranslocation,3. Ubiquitination and4. Degradation
1) RECOGNITION OF MISFOLDED OR MUTATED PROTEINSIN 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.
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.
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
CHECKPOINTS1. 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.
3) The ubiquitin-proteasome pathway1. 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 -
The ubiquitin-proteasome pathway2. The resulting activated ubiquitin is then passed to E2, which is a ubiquitin-conjugating enzyme. Biochemical Journal (2004) 379, 513-525 -
The ubiquitin-proteasome pathway3. More specifically ubiquitin protein ligases called E3, bind to the misfoldedprotein 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 -
The ubiquitin-proteasome pathway Following successive addition of ubiquitin molecules to lysine residues ofthe previously attached ubiquitin, a polyubiquitin chain is formed. Biochemical Journal (2004) 379, 513-525 -
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.
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.
ER STRESS- INDUCING CHEMICALS First group: glycosylation inhibitor Tunicamycin 2-Deoxy-D-glucose is less efficient than tunicamycin.
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.
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
RESPONSE PATHWAYS FOR ERSTRESSThe mammalian ER stress response has fourmechanisms:(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..
ENDOPLASMIC RETICULUM STORAGEDISEASES 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.
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.
DISEASES CAUSED BY PROTEIN MISFOLDING RESULTINGIN 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.
DISEASES CAUSED BY PROTEIN MISFOLDING RESULTING INDISPOSAL (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) Alzheimers 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
DISEASES CAUSED BY PROTEIN MISFOLDING RESULTING INDISPOSAL (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
DISEASES CAUSED BY PROTEIN MISFOLDING CAUSINGRETENTION/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.
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 patients lungs (emphysema) is therefore accompanied by a gain-of-toxic-function phenotype at the level of the liver (liver cirrhosis)
DISEASES CAUSED BY PROTEIN MISFOLDING CAUSINGRETENTION/DEPOSITION (GAIN OF TOXIC FUNCTION AND/OR LOSS OFFUNCTION) Protein Disease α1-Antitrypsin Liver failure, cirrhosis α-Synuclein Parkinsons 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
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 tardaSeveral (presenilin, hungtingtin, PrP,…) Neurodegenerative diseases (Alzheimers, Parkinsons, Huntingtons, Creuzfeld-Jakob) TorsinA Dystonia, myoclonic-dystonia syndrome Thyroglobulin Congenital hypothyroid goiter Wilson disease protein Wilson disease
DISEASES CAUSED BY MUTATION/OVEREXPRESSION OFER/CYTOSOLIC FACTORS INVOLVED INBIOGENESIS/DEGRADATION OF PROTEINS EXPRESSED INTHE 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.
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
DISEASES CAUSED BY MUTATION/OVEREXPRESSION OF ER/CYTOSOLICFACTORS INVOLVED IN BIOGENESIS/DEGRADATION OF PROTEINS EXPRESSEDIN THE ER Protein Disease Combined factors V/VIII deficiency, bleeding ERGIC53 disorder Glucosidase I Hypotonia and dysmorphismGlucosidase II, β-subunit/hepatocystin Polycystic liver disease Inclusion body myopathy, Pagets 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
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.