225:
151:
translating outer membrane proteins in vivo, and moreover are underrepresented on ribosomes translating inner membrane proteins. Trigger factor not only directly works to properly fold the protein but also recruits other chaperones to the ribosome, such as Hsp70. Hsp70 surrounds an unfolded peptide chain, thereby preventing aggregation and promoting folding.
66:. Cellular mechanisms for maintaining proteostasis include regulated protein translation, chaperone assisted protein folding, and protein degradation pathways. Adjusting each of these mechanisms based on the need for specific proteins is essential to maintain all cellular functions relying on a correctly folded
211:
Protein misfolding is detected by mechanisms that are specific for the cellular compartment in which they occur. Distinct surveillance mechanisms that respond to unfolded protein have been characterized in the cytoplasm, ER and mitochondria. This response acts locally in a cell autonomous fashion but
319:
The unregulated cell division that marks cancer development requires increased protein synthesis for cancer cell function and survival. This increased protein synthesis is typically seen in proteins that modulate cell metabolism and growth processes. Cancer cells are sometimes susceptible to drugs
220:
Cellular stress response pathways detect and alleviate proteotoxic stress which is triggered by imbalances in proteostasis. The cell-autonomous regulation occurs through direct detection of misfolded proteins or inhibition of pathway activation by sequestering activating components in response to
171:
The third component of the proteostasis network is the protein degradation machinery. Protein degradation occurs in proteostasis when the cellular signals indicate the need to decrease overall cellular protein levels. The effects of protein degradation can be local, with the cell only experiencing
395:
It has been suggested that this approach could even be applied prophylactically, such as upregulating certain protective pathways before experiencing an anticipated severe cellular stress. One theoretical mechanism for this approach includes upregulating the heat shock response response to rescue
378:
There are two main approaches that have been used for therapeutic development targeting the proteostatic network: pharmacologic chaperones and proteostasis regulators. The principle behind designing pharmacologic chaperones for intervention in diseases of proteostasis is to design small molecules
150:
One of the most studied ribosome binding chaperones is trigger factor. Trigger factor works to stabilize the peptide, promotes its folding, prevents aggregation, and promotes refolding of denatured model substrates. Ribosome profiling experiments have shown that TF predominantly targets ribosomes
340:
A hallmark of cellular proteostatic networks is their ability to adapt to stress via protein regulation. Metabolic disease, such as that associated with obesity, alters the ability of cellular proteostasis networks adapt to stress, often with detrimental health effects. For example, when insulin
332:
antineoplastic drugs; cancer cells either die at a lower drug concentration, or survive, depending on the type of proteins that accumulate, and the function these proteins have. Proteasome inhibitor bortezomib was the first drug of this type to receive approval for treatment of multiple myeloma.
250:(ER) is activated by imbalances of unfolded proteins inside the ER and the proteins mediating protein homeostasis. Different “detectors” - such as IRE1, ATF6 and PERK - can recognize misfolded proteins in the ER and mediate transcriptional responses which help alleviate the effects of ER stress.
237:
The cytosolic HSR is mainly mediated by the transcription factor family HSF (heat shock family). HSF is constitutively bound by Hsp90. Upon a proteotoxic stimulus Hsp90 is recruited away from HSF, which can then bind to heat response elements in the DNA and upregulate gene expression of proteins
175:
Multiple substrates are targets for proteostatic degradation. These degradable substrates include nonfunctional protein fragments produced from ribosomal stalling during translation, misfolded or unfolded proteins, aggregated proteins, and proteins that are no longer needed to carry out cellular
349:
Over time, the proteostasis network becomes burdened with proteins modified by reactive oxygen species and metabolites that induce oxidative damage. These byproducts can react with cellular proteins to cause misfolding and aggregation (especially in nondividing cells like neurons). This risk is
297:
If these effects only alter the mutated protein, the negative consequences will only be local loss of function. However, if these mutations occur in a chaperone or a protein that interacts with many other proteins, dramatic global alterations in the proteostasis boundary will occur. Examples of
391:
The principle behind proteostasis regulators is different. These molecules alter the biology of protein folding and/or degradation by altering the stoichiometry of the proteostasis network components in a given sub cellular compartment. For example, some proteostasis regulators initiate stress
382:
Previously, this approach has been used to target and stabilize G-protein coupled receptors, neurotransmitter receptors, glycosidases, lysosomal storage proteins, and the mutant CFTR protein that causes cystic fibrosis and transthyretin, which can misfiled and aggregate leading to amyloidoses.
162:
chaperonins are found in the cytosol of eukaryotic cells as well as in archaea. Group 2 chaperonins also contain an additional helical component which acts as a lid for the cylindrical protein chamber, unlike Group 1 which instead relies on an extra cochaperone to act as a lid. All chaperonins
331:
Furthermore, cancer cells tend to produce misfolded proteins, which are removed mainly by proteolysis. Inhibitors of proteolysis allow accumulation of both misfolded protein aggregates, as well as apoptosis signaling proteins in cancer cells. This can change the sensitivity of cancer cells to
293:
Dysfunction in proteostasis can arise from errors in or misregulation of protein folding. The classic examples are missense mutations and deletions that change the thermodynamic and kinetic parameters for the protein folding process. These mutations are often inherited and range in phenotypic
267:
Stress responses can also be triggered in a non-cell autonomous fashion by intercellular communication. The stress that is sensed in one tissue could thereby be communicated to other tissues to protect the proteome of the organism or to regulate proteostasis systemically. Cell non-autonomous
163:
exhibit two states (open and closed), between which they can cycle. This cycling process is important during the folding of an individual polypeptide chain as it helps to avoid undesired interactions as well as to prevent the peptide from entering into kinetically trapped states.
362:, the ensemble of chaperones and co-chaperones that interact in a complex network of molecular folding machines to regulate proteome function, is dramatically repressed in human aging brains and in the brains of patients with neurodegenerative diseases. Functional assays in
306:
Small animal model systems have been and continue to be instrumental in the identification of functional mechanisms that safeguard proteostasis. Model systems of diverse misfolding-prone disease proteins have so far revealed numerous chaperone and co-chaperone modifiers of
258:
The mitochondrial unfolded protein response detects imbalances in protein stoichiometry of mitochondrial proteins and misfolded proteins. The expression of mitochondrial chaperones is upregulated by the activation of the transcription factors ATF-1 and/or DVE-1 with UBL-5.
387:
and Pfizer sell regulatory agency approved pharmacologic chaperones for ameliorating cystic fibrosis and the transthyretin amyloidoses, respectively. Amicus sells a regulatory agency approved pharmacologic chaperone for Fabry disease–a lysosomal storage disease.
354:
to protect against these harmful aggregates, and some experimental work has suggested that upregulation of insulin growth factor receptor 1 (IGFR-1) may stabilize proteostatic network and prevent detrimental effects of aging.
122:
is a structural property that is commonly induced in this exit channel. At the same time, the exit channel prevents premature folding by impeding large scale interactions within the peptide chain that would require more space.
1274:
Lambrou GI, Papadimitriou L, Chrousos GP, Vlahopoulos SA (April 2012). "Glucocorticoid and proteasome inhibitor impact on the leukemic lymphoblast: multiple, diverse signals converging on a few key downstream regulators".
275:
has shown that neurons play a role in this intercellular communication of cytosolic HSR. Stress induced in the neurons of the worm can in the long run protect other tissues such as muscle and intestinal cells from chronic
341:
production exceeds the cell's insulin secretion capacity, proteostatic collapse occurs and chaperone production is severely impaired. This disruption leads to the disease symptoms exhibited in individuals with diabetes.
221:
heat shock. Cellular responses to this stress signaling include transcriptional activation of chaperone expression, increased efficiency in protein trafficking and protein degradation and translational reduction.
280:. Similarly ER and mitochondrial UPR in neurons are relayed to intestinal cells . These systemic responses have been implicated in mediating systemic proteostasis; they also influence organismal aging.
294:
severity from having no noticeable effect to embryonic lethality. Disease develops when these mutations render a protein significantly more susceptible to misfolding, aggregation, and degradation.
298:
diseases resulting from proteostatic changes from errors in protein folding include cystic fibrosis, Huntington's disease, Alzheimer's disease, lysosomal storage disorders, and others.
172:
effects from the loss of the degraded protein itself or widespread, with the entire protein landscape changing due to loss of other proteins’ interactions with the degraded protein.
147:
that lead to the desired folded state. Chaperones begin to assist in protein folding as soon as a nascent chain longer than 60 amino acids emerges from the ribosome exit channel.
1147:
Cohen-Kaplan V, Livneh I, Avni N, Cohen-Rosenzweig C, Ciechanover A (October 2016). "The ubiquitin-proteasome system and autophagy: Coordinated and independent activities".
179:
Several different pathways exist for carrying out these degradation processes. When proteins are determined to be unfolded or misfolded, they are typically degraded via the
154:
Chaperonins are a special class of chaperones that promote native state folding by cyclically encapsulating the peptide chain. Chaperonins are divided into two groups.
91:, a complex central to translation. Its characteristics shape the way the protein folds, and influence the protein's future interactions. The synthesis of a new
28:
1182:
Moschovi M, Critselis E, Cen O, Adamaki M, Lambrou GI, Chrousos GP, Vlahopoulos S (2015). "Drugs acting on homeostasis: challenging cancer cell adaptation".
184:
370:
sub-network of 16 chaperone genes, corresponding to 28 human orthologs as a proteostasis safeguard in aging and age-onset neurodegenerative disease.
103:
with the necessary time to become folded before the production of subsequent domains. This facilitates the correct folding of multi-domain proteins.
392:
responsive signaling, such as the unfolded protein response, which transcriptionally reprograms the endoplasmic reticulum proteostasis network.
51:, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies.
440:
Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009). "Biological and chemical approaches to diseases of proteostasis deficiency".
1530:
107:
43:
present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive
787:
Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU (2013). "Molecular chaperone functions in protein folding and proteostasis".
628:
1053:
Hipp MS, Park SH, Hartl FU (September 2014). "Proteostasis impairment in protein-misfolding and -aggregation diseases".
99:, a codon found at low concentrations in the cell. The slow synthesis rate and any such pauses provide an individual
115:
1523:
1611:
478:
Balch WE, Morimoto RI, Dillin A, Kelly JW (February 2008). "Adapting proteostasis for disease intervention".
1632:
1568:
1463:"Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation"
969:
Yébenes H, Mesa P, Muñoz IG, Montoya G, Valpuesta JM (August 2011). "Chaperonins: two rings for folding".
405:
187:(ERAD). Substrates that are unfolded, misfolded, or no longer required for cellular function can also be
111:
212:
can also extend to intercellular signaling to protect the organism from anticipated proteotoxic stress.
106:
The newly synthesized peptide chain exits the ribosome into the cellular environment through the narrow
1516:
203:(engulfment of waste products by other cells) can also be used as proteostatic degradation mechanisms.
1404:"Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade"
1575:
919:"Selective ribosome profiling reveals the cotranslational chaperone action of trigger factor in vivo"
180:
144:
1642:
140:
247:
1553:
1606:
578:
Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, et al. (December 2009).
384:
59:
350:
particularly high for intrinsically disordered proteins. The IGFR-1 pathway has been shown in
301:
110:(width: 10Ă… to 20Ă…, length 80Ă…). Characteristics of the exit channel control the formation of
95:
chain using the ribosome is very slow; the ribosome can even be stalled when it encounters a
84:
1637:
1415:
1100:"Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity"
1006:"Systemic stress signalling: understanding the cell non-autonomous control of proteostasis"
487:
325:
139:, which aid in the assembly or disassembly of proteins. They recognize exposed segments of
1075:
800:
750:
696:
453:
126:
8:
1647:
1461:
Plate L, Cooley CB, Chen JJ, Paxman RJ, Gallagher CM, Madoux F, et al. (July 2016).
132:
1419:
491:
1489:
1462:
1438:
1403:
1402:
Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, et al. (June 2012).
1379:
1355:"A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease"
1354:
1353:
Brehme M, Voisine C, Rolland T, Wachi S, Soper JH, Zhu Y, et al. (November 2014).
1300:
1251:
1226:
1207:
1124:
1099:
1030:
1005:
943:
918:
853:
828:
759:
734:
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579:
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511:
44:
32:
1331:
159:
155:
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1335:
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1199:
1164:
1129:
1080:
1035:
986:
948:
917:
Oh E, Becker AH, Sandikci A, Huber D, Chaba R, Gloge F, et al. (December 2011).
899:
858:
804:
764:
710:
660:
648:
609:
560:
531:"Chemical and biological approaches synergize to ameliorate protein-folding diseases"
503:
457:
131:
In order to maintain protein homeostasis post-translationally, the cell makes use of
1304:
1211:
515:
1484:
1474:
1433:
1423:
1374:
1366:
1327:
1318:
Adams J (December 2001). "Proteasome inhibition in cancer: development of PS-341".
1284:
1246:
1238:
1191:
1156:
1119:
1111:
1070:
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1017:
978:
938:
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889:
848:
840:
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754:
746:
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692:
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627:
Djajadikerta A, Keshri S, Pavel M, Prestil R, Ryan L, Rubinsztein DC (April 2020).
599:
591:
550:
542:
529:
Mu TW, Ong DS, Wang YJ, Balch WE, Yates JR, Segatori L, Kelly JW (September 2008).
495:
449:
321:
1195:
1370:
1160:
894:
877:
844:
1563:
1558:
1408:
Proceedings of the
National Academy of Sciences of the United States of America
982:
934:
735:"Mechanisms of cellular proteostasis: insights from single-molecule approaches"
595:
546:
308:
277:
100:
1288:
1066:
644:
629:"Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases"
143:
in the nascent peptide chain and then work to promote the proper formation of
1626:
1580:
1242:
1428:
499:
158:
chaperonins are commonly found in bacteria, chloroplasts, and mitochondria.
1498:
1447:
1388:
1339:
1296:
1260:
1203:
1168:
1133:
1084:
1039:
990:
952:
903:
862:
808:
768:
714:
652:
613:
564:
507:
461:
302:
The role of model systems in the elucidation of protein-misfolding diseases
200:
96:
1539:
119:
54:
Cellular proteostasis is key to ensuring successful development, healthy
40:
20:
1479:
1585:
1273:
1115:
192:
136:
127:
Molecular chaperones and post-translational maintenance in proteostasis
36:
1146:
580:"Reduced IGF-1 signaling delays age-associated proteotoxicity in mice"
827:
Vabulas RM, Raychaudhuri S, Hayer-Hartl M, Hartl FU (December 2010).
733:
Bustamante CJ, Kaiser CM, Maillard RA, Goldman DH, Wilson CA (2014).
367:
359:
196:
188:
48:
1508:
1021:
826:
224:
88:
67:
62:, and to minimize homeostatic perturbations from pathogens such as
24:
878:"Structure and function of the molecular chaperone Trigger Factor"
577:
166:
92:
83:
One of the first points of regulation for proteostasis is during
63:
732:
288:
191:
tagged for degradation by ATP dependent proteases, such as the
829:"Protein folding in the cytoplasm and the heat shock response"
626:
882:
Biochimica et
Biophysica Acta (BBA) - Molecular Cell Research
373:
55:
1149:
78:
1181:
87:. This regulation is accomplished via the structure of the
379:
that stabilize proteins exhibiting borderline stability.
320:
that inhibit chaperones and disrupt proteostasis, such as
253:
1352:
786:
439:
477:
1401:
1224:
968:
1225:
Sionov RV, Vlahopoulos SA, Granot Z (September 2015).
1460:
1003:
916:
268:
activation can occur for all three stress responses.
185:
endoplasmic-reticulum-associated protein degradation
875:
215:
206:
678:
396:proteins from degradation during cellular stress.
118:structures in the nascent chain. For example, an
1624:
1004:Taylor RC, Berendzen KM, Dillin A (March 2014).
232:
241:
199:, or self engulfment, lysosomal targeting, and
528:
167:Regulating proteostasis by protein degradation
1524:
1097:
1052:
238:involved in the maintenance of proteostasis.
73:
728:
726:
724:
366:and human cells have identified a conserved
289:Proteostasis and diseases of protein folding
262:
47:and degradation leading to loss-of-function
876:Hoffmann A, Bukau B, Kramer G (June 2010).
674:
672:
670:
635:. Autophagy in Neurodegenerative Diseases.
335:
283:
1531:
1517:
964:
962:
833:Cold Spring Harbor Perspectives in Biology
374:Pharmacologic intervention in proteostasis
314:
1488:
1478:
1437:
1427:
1378:
1250:
1227:"Regulation of Bim in Health and Disease"
1123:
1074:
1029:
942:
893:
852:
822:
820:
818:
758:
721:
704:
603:
554:
344:
79:The roles of the ribosome in proteostasis
679:Fedyukina DV, Cavagnero S (March 2011).
667:
435:
433:
431:
429:
427:
425:
423:
421:
223:
959:
869:
571:
473:
471:
254:Mitochondrial unfolded protein response
195:in eukaryotes or ClpXP in prokaryotes.
1625:
1346:
1010:Nature Reviews. Molecular Cell Biology
997:
815:
228:Proteostasis stress signaling response
1538:
1512:
1317:
801:10.1146/annurev-biochem-060208-092442
751:10.1146/annurev-biophys-051013-022811
697:10.1146/annurev-biophys-042910-155338
454:10.1146/annurev.biochem.052308.114844
418:
246:The unfolded protein response in the
1277:Molecular and Cellular Endocrinology
1046:
782:
780:
778:
681:"Protein folding at the exit tunnel"
468:
1184:Expert Review of Anticancer Therapy
1098:Brehme M, Voisine C (August 2016).
13:
31:includes competing and integrated
14:
1659:
775:
522:
216:Cell-autonomous stress responses
207:Signaling events in proteostasis
1454:
1395:
1311:
1267:
1218:
1175:
1140:
1104:Disease Models & Mechanisms
1091:
910:
1076:11858/00-001M-0000-0023-FD0F-4
971:Trends in Biochemical Sciences
620:
35:within cells that control the
1:
1332:10.1016/s0093-7754(01)90034-x
1196:10.1586/14737140.2015.1095095
789:Annual Review of Biochemistry
442:Annual Review of Biochemistry
411:
233:Cytosolic heat shock response
1371:10.1016/j.celrep.2014.09.042
1161:10.1016/j.biocel.2016.07.019
895:10.1016/j.bbamcr.2010.01.017
633:Journal of Molecular Biology
242:ER unfolded protein response
39:, folding, trafficking, and
7:
845:10.1101/cshperspect.a004390
739:Annual Review of Biophysics
685:Annual Review of Biophysics
406:Molecular chaperone therapy
399:
271:Work on the model organism
10:
1664:
983:10.1016/j.tibs.2011.05.003
935:10.1016/j.cell.2011.10.044
596:10.1016/j.cell.2009.11.014
547:10.1016/j.cell.2008.06.037
74:Mechanisms of proteostasis
23:of a balanced, functional
1599:
1546:
1289:10.1016/j.mce.2012.01.003
1067:10.1016/j.tcb.2014.05.003
645:10.1016/j.jmb.2019.12.035
263:Systemic stress signaling
181:unfolded protein response
1569:Renin–angiotensin system
1243:10.18632/oncotarget.5492
336:Proteostasis and obesity
284:Diseases of proteostasis
145:noncovalent interactions
1429:10.1073/pnas.1121005109
500:10.1126/science.1141448
315:Proteostasis and cancer
248:endoplasmatic reticulum
141:hydrophobic amino acids
41:degradation of proteins
1055:Trends in Cell Biology
385:Vertex Pharmaceuticals
345:Proteostasis and aging
229:
60:environmental stresses
326:proteasome inhibitors
227:
108:ribosome exit channel
1320:Seminars in Oncology
135:sometimes including
133:molecular chaperones
29:proteostasis network
1633:Biology terminology
1480:10.7554/elife.15550
1420:2012PNAS..109.9629B
492:2008Sci...319..916B
33:biological pathways
1116:10.1242/dmm.024703
358:Expression of the
230:
45:protein misfolding
21:dynamic regulation
1620:
1619:
1547:Blood composition
1540:Human homeostasis
1237:(27): 23058–134.
1655:
1612:Thermoregulation
1533:
1526:
1519:
1510:
1509:
1503:
1502:
1492:
1482:
1458:
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812:
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773:
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730:
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708:
676:
665:
664:
639:(8): 2799–2821.
624:
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607:
575:
569:
568:
558:
526:
520:
519:
475:
466:
465:
437:
322:Hsp90 inhibitors
58:, resistance to
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1643:Protein folding
1623:
1622:
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1459:
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1414:(24): 9629–34.
1400:
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1190:(12): 1405–17.
1180:
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1022:10.1038/nrm3752
1002:
998:
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929:(6): 1295–308.
915:
911:
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839:(12): a004390.
825:
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625:
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576:
572:
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486:(5865): 916–9.
476:
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317:
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291:
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265:
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1564:Blood pressure
1561:
1559:Osmoregulation
1556:
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1544:
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1535:
1528:
1521:
1513:
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1504:
1453:
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1365:(3): 1135–50.
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590:(6): 1157–69.
570:
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375:
372:
346:
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1581:Fluid balance
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1515:
1514:
1511:
1500:
1496:
1491:
1486:
1481:
1476:
1472:
1468:
1464:
1457:
1449:
1445:
1440:
1435:
1430:
1425:
1421:
1417:
1413:
1409:
1405:
1398:
1390:
1386:
1381:
1376:
1372:
1368:
1364:
1360:
1356:
1349:
1341:
1337:
1333:
1329:
1325:
1321:
1314:
1306:
1302:
1298:
1294:
1290:
1286:
1283:(2): 142–51.
1282:
1278:
1270:
1262:
1258:
1253:
1248:
1244:
1240:
1236:
1232:
1228:
1221:
1213:
1209:
1205:
1201:
1197:
1193:
1189:
1185:
1178:
1170:
1166:
1162:
1158:
1154:
1150:
1143:
1135:
1131:
1126:
1121:
1117:
1113:
1110:(8): 823–38.
1109:
1105:
1101:
1094:
1086:
1082:
1077:
1072:
1068:
1064:
1061:(9): 506–14.
1060:
1056:
1049:
1041:
1037:
1032:
1027:
1023:
1019:
1015:
1011:
1007:
1000:
992:
988:
984:
980:
977:(8): 424–32.
976:
972:
965:
963:
954:
950:
945:
940:
936:
932:
928:
924:
920:
913:
905:
901:
896:
891:
888:(6): 650–61.
887:
883:
879:
872:
864:
860:
855:
850:
846:
842:
838:
834:
830:
823:
821:
819:
810:
806:
802:
798:
794:
790:
783:
781:
779:
770:
766:
761:
756:
752:
748:
744:
740:
736:
729:
727:
725:
716:
712:
707:
702:
698:
694:
690:
686:
682:
675:
673:
671:
662:
658:
654:
650:
646:
642:
638:
634:
630:
623:
615:
611:
606:
601:
597:
593:
589:
585:
581:
574:
566:
562:
557:
552:
548:
544:
541:(5): 769–81.
540:
536:
532:
525:
517:
513:
509:
505:
501:
497:
493:
489:
485:
481:
474:
472:
463:
459:
455:
451:
447:
443:
436:
434:
432:
430:
428:
426:
424:
422:
417:
407:
404:
403:
397:
393:
389:
386:
380:
371:
369:
365:
361:
356:
353:
342:
333:
329:
327:
323:
312:
310:
299:
295:
281:
279:
274:
269:
260:
251:
249:
239:
226:
222:
213:
204:
202:
198:
194:
190:
186:
182:
177:
173:
164:
161:
157:
152:
148:
146:
142:
138:
134:
124:
121:
117:
113:
109:
104:
102:
98:
94:
90:
86:
71:
69:
65:
61:
57:
52:
50:
46:
42:
38:
34:
30:
26:
22:
18:
1591:Proteostasis
1590:
1470:
1466:
1456:
1411:
1407:
1397:
1362:
1359:Cell Reports
1358:
1348:
1326:(6): 613–9.
1323:
1319:
1313:
1280:
1276:
1269:
1234:
1230:
1220:
1187:
1183:
1177:
1152:
1148:
1142:
1107:
1103:
1093:
1058:
1054:
1048:
1016:(3): 211–7.
1013:
1009:
999:
974:
970:
926:
922:
912:
885:
881:
871:
836:
832:
792:
788:
742:
738:
688:
684:
636:
632:
622:
587:
583:
573:
538:
534:
524:
483:
479:
445:
441:
394:
390:
381:
377:
363:
357:
351:
348:
339:
330:
318:
305:
296:
292:
272:
270:
266:
257:
245:
236:
219:
210:
201:phagocytosis
178:
174:
170:
153:
149:
130:
114:and limited
105:
82:
53:
17:Proteostasis
16:
15:
1638:Homeostasis
1554:Blood sugar
1155:: 403–418.
176:function.
137:chaperonins
120:alpha helix
85:translation
1648:Proteomics
1627:Categories
1607:Predictive
1586:Hemostasis
1231:Oncotarget
795:: 323–55.
745:: 119–40.
691:: 337–59.
448:: 959–91.
412:References
364:C. elegans
352:C. elegans
273:C. elegans
193:proteasome
97:rare codon
49:phenotypes
37:biogenesis
1576:Acid–base
1473:: 15550.
661:209518157
368:chaperome
360:chaperome
197:Autophagy
189:ubiquitin
183:(UPR) or
112:secondary
1499:27435961
1448:22645360
1389:25437566
1340:11740819
1305:28749125
1297:22273806
1261:26405162
1212:28992964
1204:26523494
1169:27448843
1134:27491084
1085:24946960
1040:24556842
991:21723731
953:22153074
904:20132842
863:21123396
809:23746257
769:24895851
715:21370971
653:31887286
614:20005808
565:18775310
516:20952037
508:18276881
462:19298183
400:See also
116:tertiary
89:ribosome
68:proteome
25:proteome
1490:4954754
1439:3386102
1416:Bibcode
1380:4255334
1252:4695108
1125:5007983
1031:5922984
944:3277850
854:2982175
760:4620553
706:5807062
605:3017511
556:2650088
488:Bibcode
480:Science
160:Group 2
156:Group 1
93:peptide
64:viruses
19:is the
1497:
1487:
1446:
1436:
1387:
1377:
1338:
1303:
1295:
1259:
1249:
1210:
1202:
1167:
1132:
1122:
1083:
1038:
1028:
989:
951:
941:
902:
861:
851:
807:
767:
757:
713:
703:
659:
651:
612:
602:
563:
553:
514:
506:
460:
27:. The
1600:Other
1467:eLife
1301:S2CID
1208:S2CID
657:S2CID
512:S2CID
56:aging
1495:PMID
1444:PMID
1385:PMID
1336:PMID
1293:PMID
1257:PMID
1200:PMID
1165:PMID
1130:PMID
1081:PMID
1036:PMID
987:PMID
949:PMID
923:Cell
900:PMID
886:1803
859:PMID
805:PMID
765:PMID
711:PMID
649:PMID
610:PMID
584:Cell
561:PMID
535:Cell
504:PMID
458:PMID
1485:PMC
1475:doi
1434:PMC
1424:doi
1412:109
1375:PMC
1367:doi
1328:doi
1285:doi
1281:351
1247:PMC
1239:doi
1192:doi
1157:doi
1120:PMC
1112:doi
1071:hdl
1063:doi
1026:PMC
1018:doi
979:doi
939:PMC
931:doi
927:147
890:doi
849:PMC
841:doi
797:doi
755:PMC
747:doi
701:PMC
693:doi
641:doi
637:432
600:PMC
592:doi
588:139
551:PMC
543:doi
539:134
496:doi
484:319
450:doi
328:.
324:or
1629::
1493:.
1483:.
1469:.
1465:.
1442:.
1432:.
1422:.
1410:.
1406:.
1383:.
1373:.
1361:.
1357:.
1334:.
1324:28
1322:.
1299:.
1291:.
1279:.
1255:.
1245:.
1233:.
1229:.
1206:.
1198:.
1188:15
1186:.
1163:.
1153:79
1151:.
1128:.
1118:.
1106:.
1102:.
1079:.
1069:.
1059:24
1057:.
1034:.
1024:.
1014:15
1012:.
1008:.
985:.
975:36
973:.
961:^
947:.
937:.
925:.
921:.
898:.
884:.
880:.
857:.
847:.
835:.
831:.
817:^
803:.
793:82
791:.
777:^
763:.
753:.
743:43
741:.
737:.
723:^
709:.
699:.
689:40
687:.
683:.
669:^
655:.
647:.
631:.
608:.
598:.
586:.
582:.
559:.
549:.
537:.
533:.
510:.
502:.
494:.
482:.
470:^
456:.
446:78
444:.
420:^
311:.
70:.
1532:e
1525:t
1518:v
1501:.
1477::
1471:5
1450:.
1426::
1418::
1391:.
1369::
1363:9
1342:.
1330::
1307:.
1287::
1263:.
1241::
1235:6
1214:.
1194::
1171:.
1159::
1136:.
1114::
1108:9
1087:.
1073::
1065::
1042:.
1020::
993:.
981::
955:.
933::
906:.
892::
865:.
843::
837:2
811:.
799::
771:.
749::
717:.
695::
663:.
643::
616:.
594::
567:.
545::
518:.
498::
490::
464:.
452::
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