GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:29127155

From GONUTS
Jump to: navigation, search
Citation

Woodford, MR, Sager, RA, Marris, E, Dunn, DM, Blanden, AR, Murphy, RL, Rensing, N, Shapiro, O, Panaretou, B, Prodromou, C, Loh, SN, Gutmann, DH, Bourboulia, D, Bratslavsky, G, Wong, M and Mollapour, M (2017) Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J. 36:3650-3665

Abstract

The tumor suppressors Tsc1 and Tsc2 form the tuberous sclerosis complex (TSC), a regulator of mTOR activity. Tsc1 stabilizes Tsc2; however, the precise mechanism involved remains elusive. The molecular chaperone heat-shock protein 90 (Hsp90) is an essential component of the cellular homeostatic machinery in eukaryotes. Here, we show that Tsc1 is a new co-chaperone for Hsp90 that inhibits its ATPase activity. The C-terminal domain of Tsc1 (998-1,164 aa) forms a homodimer and binds to both protomers of the Hsp90 middle domain. This ensures inhibition of both subunits of the Hsp90 dimer and prevents the activating co-chaperone Aha1 from binding the middle domain of Hsp90. Conversely, phosphorylation of Aha1-Y223 increases its affinity for Hsp90 and displaces Tsc1, thereby providing a mechanism for equilibrium between binding of these two co-chaperones to Hsp90. Our findings establish an active role for Tsc1 as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients-including Tsc2-thereby preventing their ubiquitination and proteasomal degradation.

Links

PubMed PMC5730846 Online version:10.15252/embj.201796700

Keywords

HEK293 Cells; HSP90 Heat-Shock Proteins/genetics; HSP90 Heat-Shock Proteins/metabolism; Humans; Phosphorylation; Phosphotransferases/metabolism; Proteasome Endopeptidase Complex; Protein Folding; Proteolysis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:AHSA1

enables

GO:0001671: ATPase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P07900)

Seeded From UniProt

complete

HUMAN:AHSA1

involved_in

GO:0032781: positive regulation of ATP-dependent activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P07900)

Seeded From UniProt

complete

HUMAN:AHSA1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07900

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0016887: ATP hydrolysis activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95433

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P49815,UniProtKB:Q92574

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31948,UniProtKB:Q92574

F

Seeded From UniProt

complete

MOUSE:HS90A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8BK64

F

Seeded From UniProt

complete

HUMAN:HS90B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31948

F

Seeded From UniProt

complete

HUMAN:STIP1

part_of

GO:0101031: chaperone complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STIP1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07900

F

Seeded From UniProt

complete

HUMAN:STIP1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08238

F

Seeded From UniProt

complete

HUMAN:TEBP

part_of

GO:0101031: chaperone complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AHSA1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07901

F

Seeded From UniProt

complete

HUMAN:TSC1

part_of

GO:0101031: chaperone complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TSC1

involved_in

GO:0032780: negative regulation of ATP-dependent activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P07900)

Seeded From UniProt

complete

HUMAN:TSC1

enables

GO:0030544: Hsp70 protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TSC1

enables

GO:0042030: ATPase inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(UniProtKB:P07900)

Seeded From UniProt

complete

HUMAN:TSC1

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TSC1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07900,UniProtKB:P49815

F

Seeded From UniProt

complete

HUMAN:TSC1

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07900

F

Seeded From UniProt

complete

MOUSE:TSC1

involved_in

GO:0050821: protein stabilization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TSC1

involved_in

GO:0032780: negative regulation of ATP-dependent activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TSC1

enables

GO:0042030: ATPase inhibitor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CDC37

part_of

GO:0101031: chaperone complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0042803: protein homodimerization activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0042802: identical protein binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:HS90A

enables

GO:0016887: ATPase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TSC2

enables

GO:0051879: Hsp90 protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P07900,UniProtKB:Q92574

F

Seeded From UniProt

complete

HUMAN:PPP5

part_of

GO:0101031: chaperone complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.