Identification of two CyP-40-like cyclophilins in Saccharomyces cerevisiae, one of which is required for normal growth

Duina, Andrea A.; Marsh, James A.; Gaber, Richard F.

doi:10.1002/(sici)1097-0061(199608)12:10<943::aid-yea997>3.0.co;2-3

Cited by 79 publications

(75 citation statements)

References 54 publications

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“…Additionally, Cpr7-depleted cells are more sensitive to geldanamycin, a specific Hsp90 inhibitor, and are defective in restoring the full glucocorticoid receptor activity (30). Our results demonstrate that purified Cpr6 and Cpr7 differ in their stability, their ability to isomerase Xaa-Pro peptide bonds, and in their activity as molecular chaperones, although they share 47% sequence homology and 38% sequence identity (28). We show that, based on CD measurements and secondary structure prediction, Cpr6 and Cpr7 are predominantly ␣-helical proteins.…”

Section: Catalytic Activity Of the Large Immunophilins In The Accelermentioning

confidence: 83%

“…Previous studies have shown that the deletion of Cpr6 has no effect on the viability of yeast cells (55,29,31). In contrast, the deletion of Cpr7 caused a growth defect (28,45). Additionally, Cpr7-depleted cells are more sensitive to geldanamycin, a specific Hsp90 inhibitor, and are defective in restoring the full glucocorticoid receptor activity (30).…”

Section: Catalytic Activity Of the Large Immunophilins In The Accelermentioning

confidence: 99%

“…Although Cpr6 and Cpr7 share 47% sequence homology and 38% sequence identity (28), in vivo several differences have been found. Cpr6 and Cpr7 are both constitutively expressed, but only Cpr6 is additionally induced by heat shock (29).…”

Section: Ppiasesmentioning

confidence: 99%

“…Cpr6 and Cpr7 are both constitutively expressed, but only Cpr6 is additionally induced by heat shock (29). Depletion of Cpr7 led to a growth defect that could not be rescued by the overexpression of Cpr6 (28,30). In vitro it was shown that Cpr6 is able to catalyze the isomerization of Xaa-Pro peptide bonds (29,31), whereas Cpr7 is assumed to be inactive (32).…”

Section: Ppiasesmentioning

confidence: 99%

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Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Mayr

Richter

Lilie

et al. 2000

Journal of Biological Chemistry

106

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Hsp90 is an abundant cytosolic molecular chaperone. It controls the folding of target proteins including steroid hormone receptors and kinases in complex with several partner proteins. Prominent members of this protein family are large peptidyl prolyl cis/trans isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds in proteins and possess chaperone activity. In Saccharomyces cerevisiae, two closely related large Hsp90-associated PPIases, Cpr6 and Cpr7, exist. We show here that these homologous proteins bind with comparable affinity to Hsp90 but exhibit significant structural and functional differences. Cpr6 is more stable than Cpr7 against thermal denaturation and displays an up to 100-fold higher PPIase activity. In contrast, the chaperone activity of Cpr6 is much lower than that of Cpr7. Based on these results we suggest that the two immunophilins perform overlapping but not identical tasks in the Hsp90 chaperone cycle. PPIases1 are enzymes that are able to catalyze the cis-trans isomerization of Xaa-Pro peptide bonds in short synthetic peptides as well as in proteins (1). The isomerization of these bonds is a slow process (2) and often a rate-determining step in protein folding (3-6). PPIases have been found in all organisms and subcellular compartments studied so far (1,7,8). Until now three unrelated families of PPIases could be identified: parvulins, cyclophilins, and FKBPs (1,5,9). Because of their inhibition by the immunosuppressive drugs cyclosporin A (CsA) or FK506/rapamycin, the cyclophilins and FKBPs are also termed immunophilins (10 -13). Several large immunophilins with a molecular mass of about 40 -54 kDa are components of the Hsp90 chaperone complex. In higher eukaryotes, FKBP51, FKBP52, and Cyp40 act together with Hsp90; in yeast these are Cpr6 and Cpr7, two cyclophilins. The Hsp90 complex seems to regulate the conformation of its target proteins. These substrates include steroid hormone receptors. Here, the Hsp90 chaperone cycle is well established (reviewed in Refs. 14 -16).In the case of the progesterone receptor, the receptor is bound to Hsp70 in an early complex (15,17). Then an intermediate complex is formed in which Hsp90, Hsp70, Hip, Hop, and perhaps Hsp40 participate. The last step of this activation cycle is a complex, consisting of the progesterone receptor, Hsp90, p23, and one of the large immunophilins. The specific function of the immunophilins in the chaperone cycle is far from clear. However, it is well established that progesterone receptor has to be bound in this complex to allow binding of the hormone, dimerization, and subsequently, interaction with DNA. In the absence of hormone, the receptor is released from the complex, and the cycle starts again. The large immunophilins interact with Hsp90 via tetratricopeptide repeats (18 -21). The partner site for the tetratricopeptide-repeat motifs is located in a 12-kDa carboxyl-terminal domain of Hsp90 (22, 23). The tetratricopeptide-repeat proteins compete with each other for this binding site (18,1...

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Section: Catalytic Activity Of the Large Immunophilins In The Accelermentioning

confidence: 83%

Section: Catalytic Activity Of the Large Immunophilins In The Accelermentioning

confidence: 99%

Section: Ppiasesmentioning

confidence: 99%

Section: Ppiasesmentioning

confidence: 99%

See 2 more Smart Citations

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Mayr

Richter

Lilie

et al. 2000

Journal of Biological Chemistry

106

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“…In contrast to other co-chaperones containing a TPR domain, Cns1 is essential in yeast (4,23,(25)(26)(27)(28). Overexpression of Sti1, or of other TPR-containing proteins cannot compensate for the lethality of ⌬Cns1 (23,29). Furthermore, unlike Sti1, Cns1 expression is not up-regulated upon heat shock (23).…”

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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The tetratricopeptide repeat: a structural motif mediating protein-protein interactions

1999

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The tetratricopeptide repeat (TPR) motif is a protein‐protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three‐dimensional structural data have shown that a TPR motif contains two antiparallel α‐helices such that tandem arrays of TPR motifs generate a right‐handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR‐containing proteins are associated with multiprotein complexes, and there is extensive evidence indicating that TPR motifs are important to the functioning of chaperone, cell‐cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein‐protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932–939. © 1999 John Wiley & Sons, Inc.

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Identification of two CyP-40-like cyclophilins in Saccharomyces cerevisiae, one of which is required for normal growth

Cited by 79 publications

References 54 publications

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Cns1 Is an Activator of the Ssa1 ATPase Activity

The tetratricopeptide repeat: a structural motif mediating protein-protein interactions

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