X
Search Filters
Format Format
Format Format
X
Sort by Item Count (A-Z)
Filter by Count
Newspaper Article (59959672) 59959672
Journal Article (24754107) 24754107
Magazine Article (4001279) 4001279
Dissertation (1923620) 1923620
Book Chapter (1681256) 1681256
Book Review (1654902) 1654902
Web Resource (1430750) 1430750
Trade Publication Article (1427146) 1427146
Report (1396818) 1396818
Publication (1258994) 1258994
Newsletter (1192250) 1192250
Government Document (1033055) 1033055
Book / eBook (1007676) 1007676
Transcript (1002478) 1002478
Patent (899983) 899983
Conference Proceeding (624193) 624193
Reference (360035) 360035
Technical Report (84413) 84413
Paper (40195) 40195
Data Set (23115) 23115
Poem (16708) 16708
Art (2430) 2430
Journal / eJournal (2280) 2280
Archival Material (1543) 1543
Streaming Video (1253) 1253
Video Recording (832) 832
Electronic Resource (638) 638
Market Research (527) 527
Publication Article (526) 526
Standard (507) 507
Photograph (268) 268
Research Guide (247) 247
Presentation (197) 197
Map (180) 180
Painting (154) 154
Microfilm (132) 132
Poster (88) 88
Compact Disc (47) 47
Clothing (40) 40
Streaming Audio (40) 40
Manuscript (32) 32
Music Score (29) 29
Drawing (12) 12
Pamphlet (11) 11
Library Holding (10) 10
Computer File (8) 8
Personal Narrative (7) 7
Special Collection (7) 7
Image (6) 6
Exam (5) 5
Play (5) 5
Audio Recording (3) 3
Newspaper (3) 3
Atlas (2) 2
Kit (2) 2
Music Recording (2) 2
Graphic Arts (1) 1
Magazine (1) 1
Realia (1) 1
more...
Subjects Subjects
Subjects Subjects
X
Sort by Item Count (A-Z)
Filter by Count
humans (3477084) 3477084
index medicus (3256678) 3256678
analysis (2186506) 2186506
male (2002677) 2002677
female (1980793) 1980793
animals (1825905) 1825905
earnings per share (1583376) 1583376
stock exchanges (1494012) 1494012
corporate profits (1416448) 1416448
capital gains (1301682) 1301682
athletes (1277342) 1277342
research (1252581) 1252581
stockholders (1242728) 1242728
business metrics (1203125) 1203125
studies (1110546) 1110546
adult (1102843) 1102843
present value (1061848) 1061848
equity (1019765) 1019765
profit margins (1004629) 1004629
middle aged (942002) 942002
stock prices (935784) 935784
investments (875303) 875303
patents (871221) 871221
methods (817122) 817122
physics (734791) 734791
dividends (719461) 719461
management (716957) 716957
capital losses (701373) 701373
aged (693071) 693071
tournaments & championships (586860) 586860
market positioning (545011) 545011
education (537696) 537696
neurosciences (529358) 529358
usage (523717) 523717
biochemistry & molecular biology (503578) 503578
books (500526) 500526
market entry (494164) 494164
cancer (490536) 490536
politics (485784) 485784
materials science, multidisciplinary (485547) 485547
women (481249) 481249
health aspects (479340) 479340
chemistry (478074) 478074
inventors (475604) 475604
surgery (472392) 472392
asset acquisitions (469728) 469728
coaches & managers (467631) 467631
environmental sciences (466914) 466914
students (463261) 463261
mice (461632) 461632
return on assets (458278) 458278
boards of directors (457039) 457039
adolescent (456563) 456563
history (456529) 456529
presidents (456301) 456301
social networks (455180) 455180
rats (445707) 445707
article (439041) 439041
algorithms (422489) 422489
proteins (417350) 417350
medicine (413648) 413648
models (406077) 406077
acquisitions & mergers (396184) 396184
behavior (391044) 391044
chemistry, physical (390331) 390331
corporate profiles (387932) 387932
mathematical models (380675) 380675
risk factors (377871) 377871
life sciences (372556) 372556
time factors (368127) 368127
ecology (366075) 366075
multidisciplinary sciences (365980) 365980
care and treatment (365818) 365818
laws, regulations and rules (364818) 364818
intellectual property (361007) 361007
volatility (359983) 359983
children (359855) 359855
financial performance (354266) 354266
economics (350426) 350426
united states (348155) 348155
medical research (348111) 348111
colleges & universities (344449) 344449
electricity (344438) 344438
model (342188) 342188
short sales (340995) 340995
science (336844) 336844
cell biology (336263) 336263
medicine & public health (336089) 336089
appointments & personnel changes (333177) 333177
research article (331734) 331734
oncology (328900) 328900
software (328341) 328341
political parties (328308) 328308
child (327903) 327903
reports (324341) 324341
physiological aspects (324202) 324202
physics, applied (322878) 322878
banking industry (322118) 322118
pharmacology & pharmacy (318222) 318222
motion pictures (317380) 317380
more...
Library Location Library Location
Library Location Library Location
X
Sort by Item Count (A-Z)
Filter by Count
Robarts - Stacks (346187) 346187
UTL at Downsview - May be requested (184345) 184345
Gerstein Science - Stacks (95381) 95381
UofT at Mississauga - Stacks (61583) 61583
UofT at Scarborough - Stacks (45998) 45998
Collection Dvlpm't (Acquisitions) - Vendor file (45358) 45358
Online Resources - Online (42350) 42350
St. Michael's College (John M. Kelly) - 2nd Floor (41904) 41904
Victoria University E.J. Pratt - Stacks (35577) 35577
OISE - Stacks (29098) 29098
Trinity College (John W Graham) - Stacks (27844) 27844
Engineering & Comp. Sci. - Stacks (22541) 22541
Collection Dvlpm't (Acquisitions) - Closed Orders (21817) 21817
Thomas Fisher Rare Book - Rare Book (20506) 20506
St. Michael's College (John M. Kelly) - 3rd Floor (15578) 15578
Royal Ontario Museum - Stacks (15128) 15128
Trinity College (John W Graham) - Storage (14299) 14299
Pontifical Inst. Mediaeval Studies - Library use only (12256) 12256
Law (Bora Laskin) - Stacks (12079) 12079
Knox College (Caven) - Stacks (10071) 10071
Music - Stacks (9603) 9603
Regis College - Stacks (7910) 7910
Earth Sciences (Noranda) - Stacks (7585) 7585
Victoria University Emmanuel College - Stacks (7418) 7418
St. Augustine's Seminary - Stacks (6979) 6979
New College (Ivey) - Stacks (6853) 6853
Media Commons - Microtexts (6173) 6173
Architecture Landscape (Shore + Moffat) - Stacks (5414) 5414
University College (Laidlaw) - Stacks (5238) 5238
Mathematical Sciences - Stacks (4871) 4871
Art - Library use only (4073) 4073
Victoria University CRRS - Library use only (3816) 3816
Victoria University E.J. Pratt - Storage (3469) 3469
Royal Ontario Museum - Far Eastern (3362) 3362
Criminology - Stacks (3305) 3305
Physics - Stacks (2987) 2987
Thomas Fisher Rare Book - May be requested at Fisher (2630) 2630
UofT at Scarborough - Withdrawn (2508) 2508
Faculty of Information - Stacks (2492) 2492
Robarts - Storage (2427) 2427
Indust. Rel's & Hum. Resources (Newman) - Library use only (2380) 2380
Victoria University E.J. Pratt - Reference (2290) 2290
Institute for Christian Studies - Stacks (2244) 2244
Royal Ontario Museum - Periodical Stacks (2131) 2131
Massey College (Robertson Davies) - Rare Book (2105) 2105
Innis College - Stacks (1952) 1952
Trinity College (John W Graham) - Wycliffe Storage (1940) 1940
Victoria University Emmanuel College - Storage (1875) 1875
UofT Schools - Stacks (1862) 1862
Aerospace - Stacks (1830) 1830
Knox College (Caven) - Storage (1781) 1781
OISE - Curriculum Resources (1689) 1689
Robarts - May be requested in 6-10 wks (1583) 1583
Chemistry (A D Allen) - Stacks (1492) 1492
Astronomy & Astrophysics - Ask at library (1432) 1432
OISE - Theses (1330) 1330
Victoria University E.J. Pratt - Canadiana (1261) 1261
Faculty of Information - May be requested in 6-10 wks (1235) 1235
Trinity College (John W Graham) - Reference (1211) 1211
Providence Healthcare - Stacks (1205) 1205
Robarts - Reference (1164) 1164
OISE - May be requested in 6-10 wks (1044) 1044
Holland Bloorview Kids Rehabilitation - Stacks (1015) 1015
Baycrest Hospital - Resident/Client Library (980) 980
Engineering & Comp. Sci. - May be requested in 6-10 wks (958) 958
Victoria University Emmanuel College - Birge Storage (921) 921
Pontifical Inst. Mediaeval Studies - Guest (876) 876
Dentistry (Harry R Abbott) - Stacks (858) 858
Victoria University E.J. Pratt - Virginia Woolf (840) 840
Royal Ontario Museum - Rare Book (801) 801
University College (Laidlaw) - Purdy (757) 757
Robarts - Government Pubs (752) 752
Victoria University E.J. Pratt - Rare Book (735) 735
OISE - Storage (697) 697
UofT at Mississauga - Reference (686) 686
Robarts - Not Returned (676) 676
UofT at Scarborough - May be requested in 6-10 wks (674) 674
Victoria University E.J. Pratt - Northrop Frye (665) 665
Dentistry (Harry R Abbott) - Withdrawn (658) 658
St. Michael's College (John M. Kelly) - Reference (656) 656
Scarborough Hospital - General (643) 643
Dentistry (Harry R Abbott) - May be requested in 6-10 wks (641) 641
Gerstein Science - Theses (632) 632
Royal Ontario Museum - Far Eastern Egyptian (625) 625
East Asian (Cheng Yu Tung) - Stacks (624) 624
Map & Data - Map Collection (620) 620
Trinity College (John W Graham) - Oversize (613) 613
UofT at Mississauga - May be requested in 6-10 wks (610) 610
Royal Ontario Museum - Far Eastern West Asian (601) 601
Music - Reference (590) 590
OISE - Reference (560) 560
Richard Charles Lee Canada-Hong Kong - Library use only (559) 559
OISE - Missing (553) 553
Sunnybrook Health Sciences Centre - Sunnybrook Stacks (541) 541
Thomas Fisher Rare Book - Reference (539) 539
Gerstein Science - Reference (534) 534
East Asian (Cheng Yu Tung) - Reference (524) 524
Gardiner Museum - Library use only (504) 504
OISE - Children's Literature (488) 488
Collection Dvlpm't (Acquisitions) - Cancelled Order (482) 482
more...
Language Language
Language Language
X
Sort by Item Count (A-Z)
Filter by Count
English (103009006) 103009006
French (139932) 139932
German (125651) 125651
Korean (118027) 118027
Spanish (59785) 59785
Russian (40815) 40815
Portuguese (21202) 21202
Polish (17485) 17485
Italian (14521) 14521
Japanese (12154) 12154
Chinese (10742) 10742
Croatian (10530) 10530
Czech (7817) 7817
Latin (5165) 5165
Serbian (4806) 4806
Dutch (4335) 4335
Turkish (4042) 4042
Romanian (4038) 4038
Swedish (4029) 4029
Bosnian (3612) 3612
Arabic (3485) 3485
Norwegian (3240) 3240
Slovenian (3211) 3211
Hindi (3115) 3115
Lithuanian (3042) 3042
Hebrew (2703) 2703
Hungarian (2472) 2472
Slovak (2316) 2316
Ukrainian (2263) 2263
Urdu (2243) 2243
Danish (2147) 2147
Bulgarian (1784) 1784
Sanskrit (1780) 1780
Greek (1544) 1544
Persian (1271) 1271
Finnish (1189) 1189
Afrikaans (1158) 1158
Ancient Greek (806) 806
Indonesian (793) 793
Estonian (666) 666
Bengali (632) 632
Catalan (624) 624
Latvian (586) 586
Icelandic (293) 293
Irish (269) 269
Middle (258) 258
Albanian (234) 234
Moldavian (208) 208
Welsh (204) 204
Tamil (198) 198
Yiddish (190) 190
Panjabi (164) 164
Tibetan (151) 151
Marathi (144) 144
Macedonian (130) 130
Old English (129) 129
Old French (113) 113
Azerbaijani (102) 102
Vietnamese (102) 102
Gaelic (100) 100
Armenian (95) 95
Malay (93) 93
Kannada (92) 92
Austronesian (86) 86
Ndonga (78) 78
Malayalam (77) 77
Georgian (76) 76
Prakrit (73) 73
Nepali (70) 70
Telugu (69) 69
Pali (66) 66
Aramaic (58) 58
Ancient Egyptian (53) 53
Thai (53) 53
Maori (49) 49
Niger-Kordofanian (48) 48
American (46) 46
Indian (46) 46
Belarusian (45) 45
Gujarati (45) 45
High (45) 45
Sinhala (44) 44
Akkadian (43) 43
Oriya (43) 43
Romance (41) 41
Syriac (41) 41
Swahili (39) 39
Mongolian (38) 38
Coptic (34) 34
Basque (33) 33
Slavic (33) 33
Esperanto (32) 32
Sino-Tibetan (32) 32
Church Slavic (31) 31
Germanic (30) 30
Tagalog (30) 30
Burmese (29) 29
Indic (29) 29
Cree (26) 26
Ottoman (26) 26
more...
Publication Date Publication Date
Click on a bar to filter by decade
Slide to change publication date range


Biomedical Journal, ISSN 2319-4170, 05/2013, Volume 36, Issue 3, pp. 106 - 117
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of... 
Hsp90 | conformational cycle | clients | posttranslational modifications | ATPase | co-chaperones | Animals | HSP90 Heat-Shock Proteins - antagonists & inhibitors | HSP90 Heat-Shock Proteins - physiology | Humans | HSP90 Heat-Shock Proteins - chemistry | Protein Conformation | Protein Processing, Post-Translational | Molecular Chaperones - physiology | Signal transduction | Antibiotics | Protein folding | Breast cancer | Kinases | Machinery | Binding sites | Hsp90 can be secreted as well and it promotes tumor invasiveness. Blocking the secreted Hsp90 led to a significant inhibition of tumor metastasis. Structure of Hsp90 Top Structurally | nucleotide binding is not the only determinant for Hsp90 conformation. The interaction with co-chaperones and client protein also influences the conformational rearrangement of Hsp90. | p23/Sba1 | eNOS | in which the ATP lid is closed but the N-domains are still open. The N-terminal dimerization leads to the formation of the second intermediate state (I2) | while Hsp90β is constitutively expressed. Hsp90 analogues also exist in other cellular compartments such as Grp94 in the endoplasmic reticulum | the M-domain contributes to the interaction sites for client proteins and some co-chaperones. The C-domain is essential for the dimerization of Hsp90. Interestingly | Hsp90 works together with a large group of cofactors | the activation of its client protein | MutL (GHKL) domain ATPases | Therefore | Binding of Aha1 induces a partially closed Hsp90 conformation and accelerates the progression of the ATPase cycle dramatically. | Different from other well-known molecular chaperone like Hsp70 and GroEL/ES | Interestingly | 113 | which acts as a core modulator in plant immunity. During the recruitment and activation of NLRs | more than 200 Hsp90 client proteins have been identified (see http://www.picard.ch/downloads/Hsp90interactors.pdf ). Besides the well-studied clients such as protein kinases and SHRs | 115 | termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90 | 116 | Our understanding of the Hsp90 machinery has been greatly advanced by research of the last decades. However | 118 | Function and Regulation of the Hsp90 Machinery. Biomed J 2013;36:106-17 How to cite this URL: Li J | leading to an asymmetric intermediate complex. Hsp90 adopts the ATPase-active (closed) conformation after binding of ATP. p23/Sba1 stabilizes the closed state of Hsp90 | and protein degradation. Interestingly | the lid segment is very flexible | and the NLR protein may dissociate from Hsp90. Hsp90 complexes in RNA processing Recent studies showed that Hsp90 is also involved in the assembly of small nucleolar ribonucleoproteins (snoRNPs) and RNA polymerase. | 15 | the lid segment promotes ATP hydrolysis. Once ATP is hydrolyzed | with 1 min–1 for yeast Hsp90 and 0.1 min–1 for human Hsp90. | hyperphosphorylation also leads to a decreased Hsp90 activity. In yeast | although a TPR domain is present in Sgt1 as well | California | Germany Date of Submission 05-Sep-2012 Date of Acceptance 02-Nov-2012 Date of Web Publication 10-Jun-2013 Correspondence Address: Johannes Buchner Center for Integrated Protein Science | the M-domain in blue | which weakens the binding of Hop/Sti1 and promotes its exit from the complex. Potentially another PPIase (dashed line) associates to form the "late complex" together with Hsp90 and p23/Sba1. After the hydrolysis of ATP | posttranslational modifications of Hsp90 | and protein degradation | 125 | 5 | the protein phosphatase PP5 (yeast homologue Ppt1) | 6 | in eukaryotic Hsp90 | such as mitochondrial/chloroplast protein import (Tom70/Toc64) | 9 | In Ppt1 knockout strains | posttranslational modifications How to cite this article: Li J | Hsp90 is a homodimer and each protomer contains three flexibly linked regions | p23 is a conformation-specific co-chaperone which binds exclusively to the closed conformation of Hsp90. | 24 | viral infection | 27 | Fkbp51 | They regulate the function of Hsp90 in different ways such as inhibition and activation of the ATPase of Hsp90 as well as recruitment of specific client proteins to the cycle. Interestingly | such as double-stranded DNA protein kinase | in which the ATP lid is closed but the N-domains are still open. Then | 132 | one of the most abundant and conserved molecular chaperones | and the C-domain in orange. Click here to view Conformational dynamics of Hsp90 Top Hsp90 is a weak ATPase and the turnover rates are very low | After fast ATP binding | Hsp90 adopts a "V"- shaped form | 35 | the maturation of protein kinases also requires the Hsp70 chaperone machinery [Figure 3]B. In the early stage | Research on the assembly of Hsp90 with SHRs had shown that several distinct complexes are formed during the maturation processes. | phosphorylation affects the conformational cycle of Hsp90 | Hsp90 stabilizes and promotes the correct folding of its client proteins | recent results imply that p53 may be destabilized by Hsp90 | and ch-Hsp90 in the chloroplast. | Chaperone cycle for protein kinases Similar to SHRs | 40 | 43 | the potentiation effects do not strictly depend on the PPIase activity of Fkbp52 as PPIase-deficient mutants are also able to potentiate GR transactivation | Technical University of Munich. Lichtenbergstrasse 4 | Notably | Nucleotide binding induces directionality and a conformational cycle. | 49 | similar heterocomplexes can be found from yeast to man even in the absence of client protein. Recent studies [using FRET | PPIase | Pih1 | co-chaperone interaction | Click here to view optimized website for mobile devices Journal is indexed with MEDLINE/Index Medicus and PubMed Share on facebookShare on twitter Share on citeulike Share on googleShare on linkedin More Sharing Services Table of Contents REVIEW ARTICLE Year : 2013 | Volume : 36 | Issue : 3 | Page : 106-117 Structure | while c-Src is largely independent of Hsp90. Notably | which implies that the tight regulation of the Hsp90 phosphorylation state is necessary for the efficient processing of client proteins. Chaperone cycle for nucleotide-binding site and leucine-rich repeat domain containing (NLR) proteins NLRs are conserved immune sensors which recognize pathogens. Accumulating evidence indicates that Hsp90 and its co-chaperones Sgt1 and Rar1 are involved in the maturation of these proteins. Sgt1 interacts with the N-domain of Hsp90 through its CS domain | acetylation | It is reasonable to assume that Hsp90 recognizes certain conformations or the stability of the client protein rather than its primary sequence. Src kinase is a prominent example here. The v-Src and its cellular counterpart (c-Src) share 95% sequence identity but distinct Hsp90 dependency. The activation of v-Src strictly depends on Hsp90 | Technische Universität München | The maturation of most SHRs strictly depends on the interaction with Hsp90. Co-chaperones such as Hop/Sti1 and the large peptidylprolyl isomerase (PPIase) have strong influences on the activation. | and the NLR protein may dissociate from Hsp90. (D) Hsp90-R2TP complex. Model of the R2TP complex in yeast. Pih1 interacts with Rvb1/2 | the phosphorylation states of Hsp90 must be precisely regulated in order to maintain the proper function of Hsp90. In addition | Hsp90 reaches a more compact state | provide another level of regulation. They influence the conformational cycle | in which first one Hop/Sti1 binds to the Hsp90 dimer and stabilizes its open conformation. As a result | 59 | was also reduced consistent with the notion thatHsp90 acts as an NO sensor. This provides a feedback mechanism to inhibit further eNOS activation. Nitrosylation or mutation of the modified C-terminal cysteine residue in Hsp90 led to an ATPase-incompetent state in which the N-terminal domains are kept in the open conformation. The result indicates that nitrosylation has a profound impact on the inter-domain communication in the Hsp90 dimer. Hsp90 client protein recognition Top To date | phosphorylation also modulates the interaction with co-chaperones and thus exerts further influence on the Hsp90 machinery. For example | PDB 2CG9). The N-domain is depicted in green | Rar1 | together with Hsp90 and a PPIase. It facilitates the maturation of client proteins by stabilizing the closed conformation of Hsp90. As a result | it is indispensable for maintaining the hormone binding activity of the glucocorticoid receptor (GR) and progesterone receptor (PR). | Aha1 is the most powerful ATPase activator of Hsp90. It binds the N- and M-domains of Hsp90. | tyrosine phosphorylation on Hsp90 disrupts the interaction with Cdc37 and promotes the recruitment of Aha1. C-terminal phosphorylation of Hsp90 regulates alternate binding to co-chaperones Chip and Hop | is partially inhibited in the presence of p23/Sba1. | which facilitate the maturation of client proteins. In addition | a new model of the chaperone cycle emerges [Figure 3]A | and Hsp90 returns to the open conformation again. Figure 2: Conformational cycle of Hsp90. After fast ATP binding | c-Src kinase | and NMR-based approaches suggested that for heat-treated p53 | more than 20 co-chaperones have been identified. | we just start to understand their contributions to client protein activation. Regulation of Hsp90 by posttranslational modifications Top Posttranslational modifications are another important regulatory element of the Hsp90 machinery. Different posttranslational modifications such as phosphorylation | which is indispensable for the release of the client protein | 60 | Hsp90 and the R2TP complex are involved in the biogenesis and assembly of snoRNPs. Notably | activation | Hsp90 and Sgt1 form a ternary complex with the co-chaperone Rar1 | proposed that Hsp90-bound p53 is in a molten globule state. In contrast | while bacteria possess an Hsp90 protein | Buchner J. Structure | such as phosphorylation and acetylation | and methylation tightly control the function of Hsp90 and thus influence the maturation of client proteins. Phosphorylation Phosphorylation is the most frequently detected posttranslational modification of Hsp90. A number of different tyrosine or serine phosphorylation sites have been identified and investigated for their impact on Hsp90's chaperone function. For example | the so-called Gyrase | which determine cellular protein folding/degradation balances. Furthermore | as it contains crucial catalytic residues for forming the composite ATPase site. Moreover | According to reconstitution experiments | and the AAA+ ATPase Rvb1 and Rvb2) has been extensively investigated [Figure 3]D. | general flexibility | In yeast | Department of Chemistry | strongly influences the binding between Hsp90 and its client protein. In general | intracellular transport | Function and Regulation of the Hsp90 Machinery. Biomed J [serial online] 2013 [cited 2014 Dec 31];36:106-17. Available from: http://www.biomedj.org/text.asp?2013/36/3/106/113230 Heat shock protein 90 (Hsp90) | a middle domain (M-domain) | Another aspect which supports the idea that Hsp90 may be involved in the ubiquitin-proteasome pathway is the discovery of a protein called carboxyl terminus of Hsp70-interacting protein (CHIP). As an E3 ubiquitin ligase | and the C-domain of Tah1. Tah1 binds to the C-terminal MEEVD motif of Hsp90 through its TPR domain. Click here to view Hop/Sti1 serves as an adaptor protein between Hsp70 and Hsp90 and facilitates the transfer of client protein. | Hsc82 and Hsp82 | belong to this group. The TPR-containing PPIases contain a PPIase domain | It was originally identified in Saccharomyces cerevisiae as a gene essential for cell cycle progression. | leading to an asymmetric Hsp90 intermediate complex. After the binding of ATP and p23/Sba1 | v-Src is an aggregation-prone protein and much more sensitive to thermal and heat denaturation than c-Src. In the case of p53 | the function of PPIases in SHR complexes is not well understood. They may be selected by specific client proteins. For example | analytical ultracentrifugation (aUC) | the Hsp90 ATPase activity is inhibited. The other TPR-acceptor site is then preferentially occupied by a PPIase | the αC-β4 loop in kinases | which consists of three TPR motifs and recognizes the C-terminal MEEVD motif in Hsp90. Besides Hop/Sti1 | and steroid hormone receptors (SHRs). | mutant CFTRΔF508 | 85747 Garching Germany Login to access the Email id Crossref citations 19 PMC citations 11 DOI: 10.4103/2319-4170.113230 PMID: 23806880 Get Permissions Abstract Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction | and Cyp40 (yeast homologues Cpr6/Cpr7) | Hagn et al. reported a native-like structure of p53 interaction with Hsp90. Further analysis seems to be required to resolve this conundrum and to determine the molecular mechanism for client recognition. Hsp90 and protein degradation Top Although in general | PDB 2IOQ) and nucleotide-bound yeast Hsp90 in the closed conformation (right | In the apo state | Hsp90 reaches a fully closed state in which ATP hydrolysis occurs. After ATP is hydrolyzed | and inter-domain communication. | an N-terminal ATP-binding domain (N-domain) | bacterial Hsp90 is not essential and its precise function remains to be investigated. Recent studies suggest that it collaborates with the DnaK (Hsp70) system in substrate remodeling and may function against oxidative stress. | nitrosylation | have been discovered in recent years. | neither Hsp90 nor R2TP are components of the mature snoRNP complex. The R2TP-Hsp90 complex works together with a prefoldin-like complex in RNA polymerase II assembly. This complex interacts with unassembled Rpb1 and promotes its cytoplasmic assembly and translocation to the nucleus. In addition to the activation of client protein | 85 | CK2 protein kinase | 89 | the opening of the C-domains is anti-correlated to the closing of the N-domain. A conserved MEEVD motif at the C-terminal end serves as the docking site for the interaction with co-chaperones which contain a tetratricopeptide repeat (TPR) clamp. Figure 1: Open and closed conformation of Hsp90. Crystal structures of full-length Hsp90 from E. coli (HtpG) in the open conformation (left | release ADP as well as inorganic phosphate (Pi) | a third complex that contains a PPIase and the co-chaperone p23 had been found as the last step of the cycle. | This small acidic protein contains an unstructured C-terminal tail | Hsp90 binds the largely unfolded protein. Park et al | Histindine Kinase | which seem to be in a dynamic equilibrium [Figure 1]. | Structural studies revealed that Hsp90 spontaneously adopts structurally distinct conformations | Sgt1 has no inherent Hsp90 ATPase regulatory activity due to differences in interaction. Interestingly | many others related to | nuclear migration (NudC) | Munich | like Fkbp52 | Hsp90 adopts the "closed" conformation which weakens the binding of Hop/Sti1 and therefore promotes its exit. Another PPIase or TPR co-chaperone can potentially bind to form the final complex together with Hsp90 and p23/Sba1. Following ATP hydrolysis | biochemical experiments suggest that p53 interacts with Hsp90 in a rather folded state. | the activity of Hsp90-specific clients is significantly reduced | Hsp70 and Hsp40 interact with newly synthesized kinases. Protein kinases are recruited to Hsp90 though the action of Hop/Sti1 and the kinase-specific co-chaperone Cdc37. Both are able to stabilize the Hsp90/kinase complex. Protein phosphatase Pp5 and the ATPase activator Aha1 release Hop/Sti1 from Hsp90. At a later stage | with the M-domain of Hsp90 | co-chaperones are also involved in other physiological processes | Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function | the interaction of Cdc37 with Hsp90 leads to the stabilization of the open conformation and the inhibition of Hsp90 ATPase activity. In contrast to the co-chaperones discussed above | it is not involved in the interaction with Hsp90. Functionally | the protein phosphatase Ppt1 deletion compromised the activation of specific clients. Therefore | and a client protein form an "early complex." The client protein is transferred from Hsp70 to Hsp90 through the adaptor protein Hop/Sti1. One Hop/Sti1 bound is sufficient to stabilize the open conformation of Hsp90. The other TPR-acceptor site is preferentially occupied by a PPIase | Recent biophysical studies using ensemble and single molecule fluorescence resonance energy transfer (FRET) assays allowed to further dissect the ATP-induced conformational changes [Figure 2]. | CHIP can ubiquitinate unfolded proteins. It also interacts with the C-terminus of Hsp70 and Hsp90 through its TPR domain. | the R2TP complex (consisting of Tah1 | and a C-terminal dimerization domain (C-domain) [Figure 1]. Except for the charged linker located between the N- and M-domains in eukaryotic Hsp90 | such as formation of the active sites | several reports have shown that Hsp90 is also required for the degradation of ER membrane proteins such as cytochrome p450 2E1 | Deacetylation of Hsp90 drives the formation of Hsp90 client complexes and promotes the maturation of the client protein GR. Hsp90 can be acetylated at different sites. A study from Necker's lab pointed out that K294 | evolutionarily conserved split ATPases | Sgt1 interacts with Hsp90 as well as with an NLR protein. In the stable ternary complex | and inter-domain communications. In this review | we discuss the recent progress made in understanding the Hsp90 machinery. Keywords: ATPase | an acetylation site in the M-domain | which suggests a noncatalytic role of PPIases in the regulation of SHR signaling. In contrast to Hop/Sti1 and the TPR-PPIases | Sgt1 is promoted to interact with Hsp90 as well as with an NLR protein. In the stable ternary complex | The co-chaperone Tah1 interacts with Hsp90 through its TPR domain and its C-terminal region binds Pih1 | and electron microscopy] provided insight into how the exchange of co-chaperones is regulated. | A number of different kinases can phosphorylate Hsp90 | the N-terminal dimerization leads to the formation of the second intermediate state (I2) | it was also found to facilitate protein degradation. In addition to soluble cytosolic proteins | which leads to the final activation of protein kinases. Cdc37 is specific for chaperoning kinases. | and thus | The presence of Aha1 enables Hsp90 to bypass the I1 state and to directly reach I2 in the ATPase cycle. The activation of specific clients such as viral Src kinase (v-Src) and SHRs is severely affected in Aha1 knockout cells. Moreover | of which Hsp82 is up-regulated up to 20 times under heat stress. Hsp90α and Hsp90β are the two major isoforms in the cytoplasm of mammalian cells. Hsp90α is inducible under stress conditions | Hsp70 and Hsp40 interact with newly synthesized kinases. Protein kinases are recruited to Hsp90 through the action of Hop/Sti1 and the kinase-specific co-chaperone Cdc37. Both are able to stabilize the Hsp90/kinase complex. At a later stage | Aha1 can release Cdc37 from Hsp90 together with nucleotides. (C) Hsp90 chaperone cycle for NLRs. Rar1 binds to the N-domain of Hsp90 through its Chord1 domain and prevents the formation of the closed conformation. This interaction supports the binding of Rar1-Chord2 to the N-domain in the other protomer. With the association of Rar1-Chord2 | this domain organization is conserved from bacteria to man. Hsp90 is a member of a special class of structurally related | which is structurally similar to p23/Sba1. | called HtpG in Escherichia More Details coli | and members of the PPIase family | Mammalian Hsp90 is a target of S-nitrosylation mediated by NO produced by its client protein | Cyp40 is most abundant in estrogen receptor (ER) complexes and Fkbp52 mediates potentiation of GR through increasing GR hormone-binding affinity. Interestingly | there are two Hsp90 isoforms in the cytosol | no Hsp90 gene has been found in archea. | Johannes Buchner2 1 Division of Biology | the central player in this process | different co-chaperones work together to facilitate the maturation of Hsp90 clients. The composition of co-chaperone complexes seems to depend to some degree on the presence of a specific client protein. The chaperone cycle for SHRs Early work on Hsp90 mainly focused on the co-chaperone requirement for the activation of SHRs. | These results suggest that there may be a dynamic equilibrium between the different conformations of Hsp90 and this conformational plasticity is functionally important since it may allow Hsp90 to adapt to different client proteins. Co-chaperone regulation of Hsp90 Top Co-chaperone regulation is a conserved feature of the eukaryotic Hsp90 system. To date | which catalyzes the interconversion of the cis-trans isomerization of peptide bonds prior to proline residues and a TPR domain for the interaction with Hsp90. Most of these large PPIases show independent chaperone activity. | nuclear magnetic resonance (NMR) spectroscopy | Hsp90 does not only function in protein folding but also contribute to various cellular processes including signal transduction | which contain a Bergerat ATP-binding fold. Another interesting feature of the ATP binding region is that several conserved amino acid residues form a "lid" that closes over the nucleotide binding pocket in the ATP-bound state but is open during the ADP-bound state. The M-domain of Hsp90 is involved in ATP hydrolysis | California Institute of Technology | USA 2 Center for Integrated Protein Science | and apolipoprotein B. | innate immunity | and melanoma progression (TTC4). The above examples provide a glimpse on Hsp90 co-chaperone cycles. For some cycles | Sgt1 | Hsp90 slowly reaches the first intermediate state (I1) | is essential in eukaryotic cells. | this is not the only determinant for the interaction as other regions adjacent to the kinase domain also influence the binding to Hsp90. | Rar1 binds to the N-domain of Hsp90 through its Chord1 domain and prevents the formation of the closed conformation [Figure 3]C. This interaction supports the binding of Rar1-Chord2 to the N-domain in the other protomer. With the association of Rar1-Chord2 | Aha1 plays a critical role in the inherited misfolding disease cystic fibrosis (CF) through participating in the quality control pathway of the cystic fibrosis transmembrane conductance regulator (CFTR). Down-regulation of Aha1 could rescue the phenotype caused by misfolded CFTR. Recent research highlighted the function of Aha1 in the progression of the Hsp90 cycle. It efficiently displaces Hop/Sti1 from Hsp90 and promotes the transition from the open to closed conformation together with a PPIase in a synergistic manner. Pp5/Ppt1 is a protein phosphatase which is involved in this cycle through regulating the phosphorylation states of Cdc37. It associates with Hsp90 through its N-terminal TPR domain. Binding to Hsp90 results in the abrogation of the intrinsic inhibition of Pp5/Ppt1. Pp5/Ppt1 specifically dephosphorylates Hsp90 and Cdc37 in Hsp90 complexes. | for example | However | and Swe1Wee1 kinase. | in which the M-domain repositions and interacts with the N-domain. Then Hsp90 reaches a fully closed state in which ATP hydrolysis occurs. After ATP is hydrolyzed | Hop/Sti1 is a member of the large group of TPR co-chaperones. They contain a specialized conserved TPR-clamp domain | SHRs must pass through three complexes with different co-chaperone compositions chronologically to reach their active conformation. Hsp70/Hsp40 were identified as components in the "early complex." After association with Hsp90 through the adaptor protein Hop | and RNA modification | it became an interesting target for cancer therapy. Structurally | acetylation weakens Hsp90-client interaction | In addition to the intermediate complex | protein kinase A (PKA) | p300 was reported to be the acetyltransferase and HDAC6 acts as a deacetylase which removes the acetyl group from the protein. | Trap-1 in the mitochondrial matrix | some fundamental questions related to client proteins still remained unanswered | thus permitting access by a catalytic arginine residue of the M-domain to the ATP binding site and promoting ATP hydrolysis. Once ATP is hydrolyzed | an unstable non-TPR co-chaperone of Hsp90 [Figure 3]D. During the maturation of snoRNP | release ADP and Pi | many of them are at the same time Hsp90 client proteins. This indicates that the change of phosphorylation states of Hsp90 may influence the folding and activation of certain groups of client proteins. Acetylation Acetylation is a reversible modification mediated by opposing actions of acetyltransferases and deacetylases. Hsp90 acetylation and its influence on the chaperone machinery have been extensively investigated in recent years. In the case of Hsp90 | Hsp40 | Pasadena | and the folded client are released from Hsp90. Figure 3: Hsp90 chaperone cycles. (A) Hsp90 chaperone cycle for SHRs. Hsp70 | such as the location of the client-binding sites on Hsp90. Current evidence suggests that binding sites could be localized in each of the domains of Hsp90. Another intriguing question unsolved so far is how Hsp90 recognizes its clients. Hsp90 clients belong to different families and do not share common sequences or structural motifs. Although some regions were identified which are important for the recognition of certain group of clients | The CHIP knockdown is known to stabilize some Hsp90 clients | the ATPase activator Aha1 can release Cdc37 from Hsp90 | which is essential for its intrinsic chaperone activity. | The interaction with the Hsp90 machinery enables their correct folding | and Hsp90 returns to the open conformation. Click here to view Notably | The chaperone cycle is not completely understood yet. However | Hsp90 fails to support the activation of the client protein. Nitrosylation S-nitrosylation is a reversible covalent modification of reactive cysteine thiols in proteins by nitric oxide (NO). | Cdc37 interacts with kinases through its N-terminal domain and binds to the N-domain of Hsp90 via its C-terminal part. Similar to Hop/Sti1 | Based on these results | in which the M-domain repositions and interacts with the N-domain. Then | termed "open conformation" [Figure 1]. ATP binding triggers a series of conformational changes including repositioning of the N-terminal lid region and a dramatic change in the N-M domain orientation. Finally | endothelial nitric oxide synthase (eNOS). S-nitrosylation was reported as a negative regulator which inhibits the ATPase activity of Hsp90. In addition | p23 was identified as a component in SHR complexes | transport | we have obtained a full picture with detailed information; for others | and even degradation. | the N-domains dissociate | only phosphorylated Hsp90 stimulates the activity of the Hsp90 client protein heme-regulated inhibitor kinase (HRI); dephosphorylation eliminated the ability of Hsp90 to activate this client protein. Interestingly | the ATP hydrolysis | Hsp90 is not required for de novo folding of most proteins but facilitates the final maturation of a selected clientele of proteins. Hsp90 clients include protein kinases | the Hsp90-Tah1 complex stabilizes Pih1 in vivo and prevents its aggregation in vitro. The Tah1-Pih1 heterodimer is able to inhibit the ATPase activity of Hsp90. Tah1 and Pih1 are then transferred to the Rvb1/2 complex leading to the formation of the R2TP complex [Figure 3]D. Together | 101 | 102 | Function and Regulation of the Hsp90 Machinery Jing Li1 | termed "closed conformation" in which the N-domains are dimerized [Figure 1]. | together with nucleotides | the "intermediate complex" is formed. | p23/Sba1 and the folded client are released from Hsp90. (B) Hsp90 chaperone cycle for kinases. In the early stage | transcription factors such as p53
Journal Article
Molecular Cell, ISSN 1097-2765, 2011, Volume 41, Issue 6, pp. 672 - 681
Heat shock protein 90 (Hsp90) is an essential molecular chaperone whose activity is regulated not only by cochaperones but also by distinct posttranslational... 
YEAST | CLIENT PROTEINS | ATP HYDROLYSIS | MOLECULAR CHAPERONES | BIOCHEMISTRY & MOLECULAR BIOLOGY | IN-VIVO | CASEIN KINASE-II | STEROID-RECEPTOR | CONFORMATIONAL STATES | HEAT-SHOCK-PROTEIN | CYCLE | CELL BIOLOGY | Fungal Proteins - chemistry | Phosphorylation | Molecular Chaperones - metabolism | Saccharomyces cerevisiae - genetics | Humans | Casein Kinase II - genetics | Molecular Chaperones - chemistry | Threonine - metabolism | Recombinant Fusion Proteins - metabolism | Cell Cycle Proteins - chemistry | Saccharomyces cerevisiae - metabolism | Cell Cycle Proteins - genetics | HSP90 Heat-Shock Proteins - chemistry | HSP90 Heat-Shock Proteins - genetics | Protein Structure, Tertiary | Protein Structure, Secondary | Cell Cycle Proteins - metabolism | Molecular Chaperones - genetics | Chaperonins - chemistry | Fungal Proteins - genetics | Recombinant Fusion Proteins - chemistry | Saccharomyces cerevisiae Proteins - genetics | Chaperonins - metabolism | Saccharomyces cerevisiae Proteins - metabolism | HSP90 Heat-Shock Proteins - metabolism | Recombinant Fusion Proteins - genetics | Chaperonins - genetics | Casein Kinase II - metabolism | Fungal Proteins - metabolism | Saccharomyces cerevisiae Proteins - chemistry | Casein | Oncology, Experimental | Heat shock proteins | Amino acids | Research | Adenosine triphosphatase | Cancer
Journal Article
Nature Communications, ISSN 2041-1723, 12/2018, Volume 9, Issue 1, pp. 1472 - 14
Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established... 
ATP HYDROLYSIS | STRUCTURAL BIOLOGY | PROTEIN | TYROSINE PHOSPHORYLATION | TERMINAL DOMAIN | MULTIDISCIPLINARY SCIENCES | MACHINERY | ESCHERICHIA-COLI HSP90 | CONFORMATIONAL DYNAMICS | SACCHAROMYCES-CEREVISIAE | BINDING | Caenorhabditis elegans - chemistry | Humans | Tryptophan - chemistry | Crystallography, X-Ray | Tryptophan - metabolism | Cloning, Molecular | Escherichia coli - metabolism | HSP90 Heat-Shock Proteins - chemistry | HSP90 Heat-Shock Proteins - genetics | Lysine - metabolism | Protein Interaction Domains and Motifs | Binding Sites | Recombinant Proteins - metabolism | Amino Acid Sequence | Protein Conformation, alpha-Helical | Gene Expression | Genetic Vectors - chemistry | Adenosine Triphosphatases - metabolism | Genetic Vectors - metabolism | Recombinant Proteins - chemistry | Recombinant Proteins - genetics | Molecular Dynamics Simulation | Saccharomyces cerevisiae - chemistry | Sequence Alignment | Animals | Protein Conformation, beta-Strand | Escherichia coli - genetics | Zebrafish - metabolism | HSP90 Heat-Shock Proteins - metabolism | Protein Binding | Adenosine Triphosphatases - chemistry | Ligands | Adenosine Triphosphatases - genetics | Mice | Structural Homology, Protein | Mutation | Lysine - chemistry | Amino Acid Substitution | Proteins | Hsp90 protein | Lysine | Tryptophan | Heat shock proteins | Heat shock
Journal Article
The EMBO Journal, ISSN 0261-4189, 12/2017, Volume 36, Issue 24, pp. 3650 - 3665
Journal Article