CPR6

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Research report: CPR6 (YLR216C; UniProt P53691) in Saccharomyces cerevisiae (S288c)

0) Target verification (critical identity check)

The literature analyzed here explicitly refers to Saccharomyces cerevisiae CPR6/YLR216C, encoding a cyclophilin 40 (CyP40)-like peptidyl-prolyl cis–trans isomerase with an N-terminal cyclophilin/PPIase domain and a C-terminal TPR domain, matching UniProt accession P53691 and the domain architecture you provided (PPIase + TPR repeats) (dolinski1998cns1encodesan pages 1-2, duina1996identificationoftwo pages 1-2, tenge2015thehsp90cochaperones pages 1-2).

1) Key concepts and definitions (current understanding)

1.1 Cyclophilins and PPIase activity

Cyclophilins are peptidyl-prolyl cis–trans isomerases (PPIases; EC 5.2.1.8) that catalyze the interconversion of cis/trans conformations at Xaa–Pro peptide bonds, which can be rate-limiting during protein folding (mayr2000cpr6andcpr7 pages 1-1). In the yeast Hsp90 system, cyclophilins of the CyP40 class (including Cpr6 and Cpr7) are “large immunophilins” that couple a cyclophilin domain to TPR repeats, enabling docking to Hsp90 (mayr2000cpr6andcpr7 pages 1-1, dolinski1998cns1encodesan pages 1-2).

1.2 TPR domains and Hsp90 cochaperones

Many Hsp90 cochaperones contain tetratricopeptide repeats (TPRs) that bind the conserved C-terminal MEEVD motif of Hsp90, mediating a regulated exchange of cochaperones during the ATP-dependent Hsp90 folding cycle (tenge2015thehsp90cochaperones pages 1-2, dolinski1998cns1encodesan pages 1-2). CPR6 is one of these TPR cochaperones and is considered part of the cytosolic Hsp90 chaperone machine (tenge2015thehsp90cochaperones pages 1-2, mayr2000cpr6andcpr7 pages 1-1).

2) CPR6 protein architecture, localization, and interaction network

2.1 Domain architecture (what CPR6 encodes)

Cpr6 contains a PPIase domain plus a TPR domain “flanked by charged regions,” consistent with a dual enzymatic + cochaperone/adaptor role (tenge2015thehsp90cochaperones pages 1-2). A figure mapping truncations/mutations and their effects on interactions shows that the C-terminal region is crucial for ribosome association and helps resolve which regions drive Hsp90 vs ribosome binding (tenge2015thehsp90cochaperones media e3c93753).

2.2 Subcellular context / where CPR6 acts

The retrieved experimental evidence places Cpr6 primarily in the cytosolic proteostasis network through its association with cytosolic Hsp90 (explicitly described as a cytosolic chaperone) and through a direct physical association with intact ribosomes (mayr2000cpr6andcpr7 pages 1-1, tenge2015thehsp90cochaperones pages 1-2). Specifically, purification of Cpr6 copurified multiple ribosomal proteins from both small and large subunits, demonstrating ribosome association rather than a purely soluble Hsp90 complex membership (tenge2015thehsp90cochaperones pages 1-2, tenge2015thehsp90cochaperones pages 5-6).

2.3 Protein–protein interactions (directly supported)

Key experimentally supported partners/associations include:
- Hsp90: Cpr6 binds Hsp90 in biochemical pull-down experiments (GST-Cpr6 can recover Hsp90 from yeast or bacterial lysates expressing Hsp90) (duina1996acyclophilinfunction pages 1-2). The broader cochaperone framework also predicts TPR-mediated Hsp90 tail binding (dolinski1998cns1encodesan pages 1-2).
- Hsp70: Cpr6 isolates can copurify Hsp70 as part of cochaperone/client-associated complexes (tenge2015thehsp90cochaperones pages 1-2).
- Ura2 (Hsp90 client): Cpr6 purification copurifies Ura2, an Hsp90 client required for pyrimidine biosynthesis, linking Cpr6 to client-facing Hsp90 function (tenge2015thehsp90cochaperones pages 1-2).
- Ribosome: Cpr6 interacts with intact ribosomes; only Cpr6 (among tested cochaperones in that study) and Zuo1 showed robust ribosome interaction (tenge2015thehsp90cochaperones pages 5-6).
- Cns1/Cpr7 network differences: In classic complex isolation work, Cns1 was detected in complexes with Hsp90 and Cpr7, but not with Cpr6, implying paralog-specific wiring of Hsp90 cochaperone subcomplexes (dolinski1998cns1encodesan pages 1-2).

3) Primary molecular function: catalysis and substrate specificity

3.1 Catalyzed reaction

Cpr6’s primary enzymatic activity is peptidyl-prolyl cis–trans isomerization at Xaa–Pro bonds (PPIase activity) (mayr2000cpr6andcpr7 pages 1-1).

3.2 Substrate specificity (what is known)

The retrieved texts support the general cyclophilin substrate class (Xaa–Pro peptide bonds) but do not provide a CPR6-specific physiological substrate list; instead, they emphasize its integration into Hsp90-dependent client maturation and ribosome-associated proteostasis (mayr2000cpr6andcpr7 pages 1-1, tenge2015thehsp90cochaperones pages 1-2). The best-supported “substrate context” is therefore: (i) folding intermediates/clients handled by Hsp90, and (ii) proteins associated with translation machinery via ribosome binding (tenge2015thehsp90cochaperones pages 1-2, tenge2015thehsp90cochaperones pages 5-6).

3.3 Quantitative biochemical properties (directly stated)

• Relative PPIase strength: Cpr6 displays up to ~100-fold higher PPIase activity than Cpr7 (mayr2000cpr6andcpr7 pages 1-1).
• Chaperone activity comparison: Cpr6 has much lower intrinsic chaperone activity than Cpr7, despite higher PPIase activity, implying functional specialization between paralogs (mayr2000cpr6andcpr7 pages 1-1).

4) CPR6 function in pathways/biological processes

4.1 Role as an Hsp90 cochaperone (mechanistic framing)

Cpr6 is best described as an Hsp90-associated immunophilin cochaperone that regulates the Hsp90 folding cycle through TPR-mediated association and (in at least some contexts) through conformational control of Hsp90 states (mayr2000cpr6andcpr7 pages 1-1, mercier2023hsp90mutantswith pages 1-2).

A 2023 yeast genetics study using distinct Hsp90 conformational mutants supports a model in which Hch1 destabilizes Hsp90–nucleotide interaction and hinders formation of the closed conformation, while Cpr6 counteracts Hch1 by stabilizing the closed conformation (mercier2023hsp90mutantswith pages 1-2). This positions Cpr6 as a regulator of the timing of transitions in the Hsp90 cycle, rather than merely an accessory enzyme (mercier2023hsp90mutantswith pages 1-2).

4.2 Link to translation: ribosome association and proteostasis

Tenge et al. provide strong evidence that Cpr6 is a ribosome-interacting Hsp90 cochaperone, describing this as a “novel link between the Hsp90 molecular-chaperone machine and protein synthesis” (tenge2015thehsp90cochaperones pages 1-2). Functionally:
- The TPR + flanking region contains distinct binding sites for Hsp90, Ura2, and the ribosome (tenge2015thehsp90cochaperones pages 5-6).
- Truncation or alteration of basic residues near the C-terminus disrupts ribosome interaction (tenge2015thehsp90cochaperones pages 1-2).
- CPR6 overexpression phenotypes in sensitized backgrounds depend on intact Hsp90/ribosome interaction (tenge2015thehsp90cochaperones pages 5-6).

5) Genetics and phenotypes (what perturbing CPR6 does)

5.1 Viability and baseline growth

Yeast lacking CPR6 are viable and in multiple reports show no obvious/noticeable growth defect under standard conditions, in contrast to CPR7 and CNS1 perturbations (dolinski1998cns1encodesan pages 1-2, tenge2015thehsp90cochaperones pages 1-2).

5.2 Context-dependent phenotypes (interaction with the cochaperone network)

• In a temperature-sensitive cns1-G90D background, overexpression of CPR6 exacerbates growth defects, and Cpr6 mutants defective in ribosome interaction fail to produce this negative effect (tenge2015thehsp90cochaperones pages 1-2, tenge2015thehsp90cochaperones pages 5-6).
• In translation-stress assays, loss of CPR7 or CNS1 mutations confer hygromycin sensitivity, whereas CPR6 deletion did not under the tested conditions, suggesting non-identical contributions of CyP40 paralogs to translation-linked stress phenotypes (tenge2015thehsp90cochaperones pages 5-6).

5.3 Hsp90-dependent signal transduction clients (client-specific outputs)

A seminal study on Hsp90-dependent signaling in yeast provides client-selective phenotypes:
- Glucocorticoid receptor (GR): deleting CPR6 did not reduce hormone-dependent GR activity (in contrast to CPR7 deletion, which reduced GR activity markedly) (duina1996acyclophilinfunction pages 1-2).
- Oncogenic tyrosine kinase (v-Src/pp60v-src-like client): in cpr6Δ cells, kinase activity decreased by ~50% while accumulation was unaffected, consistent with a role in client maturation/activation rather than expression (duina1996acyclophilinfunction pages 1-2).
These results support the concept that Cpr6 participates in the Hsp90 system but is not uniformly required for all Hsp90 clients; instead, it can have client- and context-specific effects (duina1996acyclophilinfunction pages 1-2, mayr2000cpr6andcpr7 pages 1-1).

6) Recent developments (2023–2024) and expert analysis

Recent work increasingly frames cochaperones (including Cpr6) as regulators of Hsp90 conformational transitions and client fate. Key 2023–2024 advances captured in the retrieved corpus are summarized below.

Table: This table summarizes 2023–2024 papers and reviews most relevant to yeast CPR6 within the Hsp90 cochaperone system. It highlights recent mechanistic advances, quantitative context, and publication details useful for functional annotation.

Two particularly relevant “expert interpretation” points from 2023–2024 sources are:
1) Conformational regulation over ATPase-centric models: Mercier et al. argue that timing of transitions into/out of Hsp90 closed conformations is tightly regulated by cochaperones, including Cpr6, shifting emphasis from ATPase rate alone toward conformational control (mercier2023hsp90mutantswith pages 1-2).
2) Proteostasis scale and translation linkage: Fulton et al. emphasize that Hsp90 supports a substantial fraction of the proteome and that cochaperone networks interact with translation fidelity pathways; although their focal client is eEF2 and other cochaperones (e.g., Cpr7, Cns1, Hgh1), the paper explicitly situates CPR6 within the cochaperone landscape being interrogated (fulton2024hsp90andcochaperones pages 1-2).

7) Quantitative/statistical highlights (recent studies and key primary results)

• Proteome fraction: Hsp90 is reported to be required for maintaining ~20% of the yeast proteome in an active, folded conformation (fulton2024hsp90andcochaperones pages 1-2). This statistic provides the “systems” context in which cochaperones like Cpr6 operate.
• Protein abundance estimates (per cell): Hsp90 (Hsc82/Hsp82) is estimated at ~229,000 molecules per cell and eEF2 at 145,000 molecules per cell (fulton2024hsp90andcochaperones pages 1-2).
• Client effect size (CPR6 deletion): ~50% decrease in activity of an oncogenic tyrosine kinase client in cpr6Δ cells (duina1996acyclophilinfunction pages 1-2).
• PPIase magnitude (paralog comparison): Cpr6 has up to ~100-fold higher PPIase activity than Cpr7 (mayr2000cpr6andcpr7 pages 1-1).
• Domain mapping / construct-based quantitation: A functionally critical Cpr6 region spanning aa 171–371 was sufficient for strong overexpression-linked growth effects in a sensitized background, even without the PPIase domain, indicating that at least some in vivo phenotypes are mediated by non-catalytic regions (tenge2015thehsp90cochaperones pages 5-6).

8) Current applications and real-world implementations

8.1 Yeast CPR6 as a tractable model for conserved Hsp90–cochaperone biology

The most mature real-world “implementation” is methodological: yeast provides a genetically powerful system to dissect conserved chaperone mechanisms and to map cochaperone-specific regulation. CPR6 is repeatedly used as part of that cochaperone toolkit, enabling inference relevant to eukaryotic Hsp90 systems broadly (rios2024insightsintohsp90 pages 1-2, mercier2023hsp90mutantswith pages 1-2).

8.2 Drug-mechanism relevance via Hsp90 inhibitor studies

Although CPR6 is not itself presented as a clinical target in the retrieved corpus, yeast systems that include CPR6 are directly used to interpret cellular consequences of Hsp90 inhibitors. For example, the anticancer Hsp90 inhibitor NVP-AUY922 (luminespib) is discussed in the context of yeast Hsp90 conformational mutants; cochaperone balance (including Cpr6) helps interpret how conformational progression relates to inhibitor sensitivity (mercier2023hsp90mutantswith pages 1-2).

9) Summary: best-supported functional annotation (evidence-weighted)

Table: This table summarizes the experimentally supported functional annotation of yeast CPR6, emphasizing domain architecture, molecular and cochaperone activities, interaction partners, ribosome linkage, phenotypes, and quantitative findings most relevant for gene annotation.

Evidence-weighted functional statement:
CPR6 encodes a nonessential cytosolic CyP40-like cyclophilin whose most strongly supported functions are (i) PPIase catalysis of Xaa–Pro bond isomerization, (ii) TPR-mediated participation in the Hsp90 cochaperone network (including regulation of Hsp90 conformational cycling), and (iii) physical association with intact ribosomes linking Hsp90 cochaperone function to translation-associated proteostasis (mayr2000cpr6andcpr7 pages 1-1, tenge2015thehsp90cochaperones pages 1-2, mercier2023hsp90mutantswith pages 1-2).

10) Key supporting figure

A domain/interactions schematic and mapping of Cpr6 determinants for Hsp90 vs ribosome association is shown in Tenge et al. (2015) (tenge2015thehsp90cochaperones media e3c93753).

References (URLs and publication dates where available)

• Duina AA et al. Identification of two CyP-40-like cyclophilins in Saccharomyces cerevisiae… Yeast. 1996. https://doi.org/10.1002/(sici)1097-0061(199608)12:10<943::aid-yea997>3.0.co;2-3 (duina1996identificationoftwo pages 1-2)
• Duina AA et al. A cyclophilin function in Hsp90-dependent signal transduction. Science. 1996. https://doi.org/10.1126/science.274.5293.1713 (duina1996acyclophilinfunction pages 1-2)
• Dolinski KJ et al. CNS1 Encodes an Essential p60/Sti1 Homolog… Molecular and Cellular Biology. 1998. https://doi.org/10.1128/mcb.18.12.7344 (dolinski1998cns1encodesan pages 1-2)
• Mayr C et al. Cpr6 and Cpr7… differ in their functional properties. J Biol Chem. 2000. https://doi.org/10.1074/jbc.M005251200 (mayr2000cpr6andcpr7 pages 1-1)
• Tenge VR et al. The Hsp90 Cochaperones Cpr6, Cpr7, and Cns1 Interact with the Intact Ribosome. Eukaryotic Cell. Jan 2015. https://doi.org/10.1128/EC.00170-14 (tenge2015thehsp90cochaperones pages 1-2)
• Mercier R et al. Hsp90 mutants with distinct defects provide novel insights into cochaperone regulation of the folding cycle. PLOS Genetics. May 25, 2023. https://doi.org/10.1371/journal.pgen.1010772 (mercier2023hsp90mutantswith pages 1-2)
• Rios EI et al. Insights into Hsp90 mechanism and in vivo functions learned from studies in the yeast, Saccharomyces cerevisiae. Frontiers in Molecular Biosciences. Feb 8, 2024. https://doi.org/10.3389/fmolb.2024.1325590 (rios2024insightsintohsp90 pages 1-2)
• Fulton MD et al. Hsp90 and cochaperones have two genetically distinct roles in regulating eEF2 function. PLOS Genetics. Dec 9, 2024. https://doi.org/10.1371/journal.pgen.1011508 (fulton2024hsp90andcochaperones pages 1-2)

References

1. (dolinski1998cns1encodesan pages 1-2): Kara J. Dolinski, Maria E. Cardenas, and Joseph Heitman. Cns1 encodes an essential p60/sti1 homolog in saccharomyces cerevisiae that suppresses cyclophilin 40 mutations and interacts with hsp90. Molecular and Cellular Biology, 18:7344-7352, Dec 1998. URL: https://doi.org/10.1128/mcb.18.12.7344, doi:10.1128/mcb.18.12.7344. This article has 122 citations and is from a domain leading peer-reviewed journal.

2. (duina1996identificationoftwo pages 1-2): Andrea A. Duina, James A. Marsh, and Richard F. Gaber. Identification of two cyp‐40‐like cyclophilins in saccharomyces cerevisiae, one of which is required for normal growth. Yeast, 12:943-952, Aug 1996. URL: https://doi.org/10.1002/(sici)1097-0061(199608)12:10<943::aid-yea997>3.0.co;2-3, doi:10.1002/(sici)1097-0061(199608)12:10<943::aid-yea997>3.0.co;2-3. This article has 119 citations and is from a peer-reviewed journal.

3. (tenge2015thehsp90cochaperones pages 1-2): Victoria R. Tenge, Abbey D. Zuehlke, Neelima Shrestha, and Jill L. Johnson. The hsp90 cochaperones cpr6, cpr7, and cns1 interact with the intact ribosome. Eukaryotic Cell, 14:55-63, Jan 2015. URL: https://doi.org/10.1128/ec.00170-14, doi:10.1128/ec.00170-14. This article has 23 citations and is from a peer-reviewed journal.

4. (mayr2000cpr6andcpr7 pages 1-1): Christian Mayr, Klaus Richter, Hauke Lilie, and Johannes Buchner. Cpr6 and cpr7, two closely related hsp90-associated immunophilins from saccharomyces cerevisiae, differ in their functional properties*. The Journal of Biological Chemistry, 275:34140-34146, Nov 2000. URL: https://doi.org/10.1074/jbc.m005251200, doi:10.1074/jbc.m005251200. This article has 152 citations.

5. (tenge2015thehsp90cochaperones media e3c93753): Victoria R. Tenge, Abbey D. Zuehlke, Neelima Shrestha, and Jill L. Johnson. The hsp90 cochaperones cpr6, cpr7, and cns1 interact with the intact ribosome. Eukaryotic Cell, 14:55-63, Jan 2015. URL: https://doi.org/10.1128/ec.00170-14, doi:10.1128/ec.00170-14. This article has 23 citations and is from a peer-reviewed journal.

6. (tenge2015thehsp90cochaperones pages 5-6): Victoria R. Tenge, Abbey D. Zuehlke, Neelima Shrestha, and Jill L. Johnson. The hsp90 cochaperones cpr6, cpr7, and cns1 interact with the intact ribosome. Eukaryotic Cell, 14:55-63, Jan 2015. URL: https://doi.org/10.1128/ec.00170-14, doi:10.1128/ec.00170-14. This article has 23 citations and is from a peer-reviewed journal.

7. (duina1996acyclophilinfunction pages 1-2): Andrea A. Duina, Hui-Chen Jane Chang, James A. Marsh, Susan Lindquist, and Richard F. Gaber. A cyclophilin function in hsp90-dependent signal transduction. Science, 274:1713-1715, Dec 1996. URL: https://doi.org/10.1126/science.274.5293.1713, doi:10.1126/science.274.5293.1713. This article has 275 citations and is from a highest quality peer-reviewed journal.

8. (mercier2023hsp90mutantswith pages 1-2): Rebecca Mercier, Danielle Yama, Paul LaPointe, and Jill L. Johnson. Hsp90 mutants with distinct defects provide novel insights into cochaperone regulation of the folding cycle. PLOS Genetics, 19:e1010772, May 2023. URL: https://doi.org/10.1371/journal.pgen.1010772, doi:10.1371/journal.pgen.1010772. This article has 13 citations and is from a domain leading peer-reviewed journal.

9. (rios2024insightsintohsp90 pages 1-2): Erick I. Rios, Isabel L. Hunsberger, and Jill L. Johnson. Insights into hsp90 mechanism and in vivo functions learned from studies in the yeast, saccharomyces cerevisiae. Frontiers in Molecular Biosciences, Feb 2024. URL: https://doi.org/10.3389/fmolb.2024.1325590, doi:10.3389/fmolb.2024.1325590. This article has 8 citations.

10. (fulton2024hsp90andcochaperones pages 1-2): Melody D. Fulton, Danielle J. Yama, Ella Dahl, and Jill L. Johnson. Hsp90 and cochaperones have two genetically distinct roles in regulating eef2 function. PLOS Genetics, 20:e1011508, Dec 2024. URL: https://doi.org/10.1371/journal.pgen.1011508, doi:10.1371/journal.pgen.1011508. This article has 5 citations and is from a domain leading peer-reviewed journal.

11. (forafonov2008p23sba1pprotectsagaints pages 26-30): F Forafonov. P23/sba1p protects againts hsp90 inhibitors. Unknown journal, 2008.

Citations

1. duina1996acyclophilinfunction pages 1-2
2. duina1996identificationoftwo pages 1-2
3. https://doi.org/10.1371/journal.pgen.1010772
4. https://doi.org/10.1042/EBC20220224
5. https://doi.org/10.3389/fmolb.2024.1325590
6. https://doi.org/10.1371/journal.pgen.1011508
7. https://doi.org/10.1007/s12192-023-01342-z
8. https://doi.org/10.1002/(sici
9. https://doi.org/10.1128/mcb.18.12.7344;
10. https://doi.org/10.1128/EC.00170-14
11. https://doi.org/10.1074/jbc.M005251200;
12. https://doi.org/10.1128/mcb.18.12.7344
13. https://doi.org/10.1371/journal.pgen.1010772;
14. https://doi.org/10.1074/jbc.M005251200
15. https://doi.org/10.1128/EC.00170-14;
16. https://doi.org/10.1126/science.274.5293.1713
17. https://doi.org/10.3389/fmolb.2024.1325590;
18. https://doi.org/10.1128/mcb.18.12.7344,
19. https://doi.org/10.1128/ec.00170-14,
20. https://doi.org/10.1074/jbc.m005251200,
21. https://doi.org/10.1126/science.274.5293.1713,
22. https://doi.org/10.1371/journal.pgen.1010772,
23. https://doi.org/10.3389/fmolb.2024.1325590,
24. https://doi.org/10.1371/journal.pgen.1011508,