Structure of TPR Domain–Peptide Complexes

Scheufler, Clemens; Brinker, Achim; Bourenkov, Gleb; Pegoraro, Stefano; Moröder, Luis; Bartunik, H.D.; Hartl, F. Ulrich; Moarefi, Ismail

doi:10.1016/s0092-8674(00)80830-2

Cited by 1,090 publications

(612 citation statements)

References 42 publications

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“…The TPR, first described in yeast proteins (41,42), is a tandem 34-amino acid repeat composed of antiparallel ␣-helices (30). The TPR domains of CHIP mediate its interaction with Hsp90 and Hsp70 to redirect incompletely folded proteins for degradation (31).…”

Section: Discussionmentioning

confidence: 99%

“…The TPR domains of CHIP mediate its interaction with Hsp90 and Hsp70 to redirect incompletely folded proteins for degradation (31). TPR protein interaction surfaces on the chaperone cofactors Hip (Hsp70-interacting protein) (43) and Hop (Hsp90/Hsp70-organizing protein) (44) interact with the COOH-terminal EEVD motif of Hsp70 and Hsp90 during the chaperone heterocomplex formation that mediates protein folding (30,45,46). CHIP inhibits Hsp70 ATPase and protein refolding activities, although paradoxically, its overexpression increases chaperone activity (47).…”

Section: Discussionmentioning

confidence: 99%

“…The AR interaction with CHIP was eliminated by deleting the CHIP TPR domain (lane 6), by deleting the CHIP U-box domain (lane 7), or by introducing a K30A mutation into the CHIP TPR domain (lane 8). Lys 30 is highly conserved in the TPR domain (30) and was shown to be required for the interaction between the CHIP TPR domain and Hsp70 or Hsp90. 5 Two AR mutations identified in the transgenic adenocarcinoma of mouse prostate (TRAMP) model for prostate cancer, E236G and A234T (17), also reduced the AR and CHIP interaction by 43 and 16%, respectively (Fig.…”

Section: Fig 3 Interaction Of Chip With the Ar Nh 2 -Terminal Consementioning

confidence: 99%

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An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

122

113

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The NH 2 -terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH 2 -terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH 2 -terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH 2 -terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH 2 -terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH 2 -terminal domains and other intrinsically unstructured transcriptional regulatory proteins.Steroid receptors depend on multiple domains for their function as ligand-dependent transcriptional activators. The DNAand ligand-binding domains have been studied extensively and have a high degree of structural and functional conservation. In contrast, the largely unstructured NH 2 -terminal domains (1-3) are highly variable in size and sequence, and the molecular mechanisms that contribute to transactivation are not well understood. The size of the NH 2 -terminal region of steroid receptors increases with evolutionary expansion (4, 5), from estrogen receptor-␣ (185 amino acid residues) to the glucocorticoid receptor (GR 1 ; 420 residues), androgen receptor (AR; 558 residues), progesterone receptor (B form; 566 residues), and mineralocorticoid receptor (602 residues). In contrast, transcription factors such as p53, NF-B, and VP16 typically have transcriptional activation domains of Ͻ100 residues.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Fig 3 Interaction Of Chip With the Ar Nh 2 -Terminal Consementioning

confidence: 99%

See 1 more Smart Citation

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

122

113

View full text Add to dashboard Cite

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“…In the case of Hsp90 and Hsp70/Ssa1, binding of their highly conserved C-terminal residues EEVD to TPR domains is based predominantly on a "carboxylate clamp," which anchors the aspartate via electrostatic interactions to a conserved set of side chains inside this groove. The TPR domain of Cns1 (cyclophilin seven suppressor) can be expected to form this clamp, since the residues Lys 87 , Asn 91 , Asn 126 , Lys 156 , and Arg 160 agree with the respective consensus sequence (22). Several Hsp90 co-chaperones, including the prolyl isomerases Cpr6 and Cpr7, Ppt1 (protein phosphatase 1), and the protein Cns1 contain TPR motifs.…”

mentioning

confidence: 99%

Cns1 Is an Activator of the Ssa1 ATPase Activity

Hainzl¹,

Wegele²,

Richter

et al. 2004

Journal of Biological Chemistry

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Hsp90 is a key mediator in the folding process of a growing number of client proteins. The molecular chaperone cooperates with many co-chaperones and partner proteins to fulfill its task. In Saccharomyces cerevisiae, several co-chaperones of Hsp90 interact with Hsp90 via a tetratricopeptide repeat (TPR) domain. Here we show that one of these proteins, Cns1, binds both to Hsp90 and to the yeast Hsp70 protein Ssa1 with comparable affinities. This is reminiscent of Sti1, another TPR-containing co-chaperone. Unlike Sti1, Cns1 exhibits no influence on the ATPase of Hsp90. However, it activates the ATPase of Ssa1 up to 30-fold by accelerating the ratelimiting ATP hydrolysis step. This stimulating effect is mediated by the N-terminal TPR-containing part of Cns1, whereas the C-terminal part showed no effect. Competition experiments allow the conclusion that Hsp90 and Ssa1 compete for binding to the single TPR domain of Cns1. Taken together, Cns1 is a potent cochaperone of Ssa1. Our findings highlight the importance of the regulation of Hsp70 function in the context of the Hsp90 chaperone cycle.

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“…TPR are degenerate 34 amino acid repeats often associated with protein-protein interactions (Blatch and Lassle, 1999), and are present in diverse proteins important e.g. for cell cycle regulation (Lamb et al, 1994), transcription (Gounalaki et al, 2000;Nakatsu et al, 2000), and also in chaperone complexes (Scheufler et al, 2000). The presence of TPR domains in NATH suggests that this protein may be part of a multiprotein complex.…”

Section: Discussionmentioning

confidence: 99%