FK506 Binding Protein from a Thermophilic Archaeon, <i>Methanococcus thermolithotrophicus</i>, Has Chaperone-like Activity in Vitro

Furutani, Masahiro; Ideno, Akira; Iida, Toshii; Maruyama, Tadashi

doi:10.1021/bi9911076

Cited by 38 publications

(56 citation statements)

References 35 publications

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“…It has been suggested that the chaperone activity resides in domains outside the PPIase domain (35). Interestingly, for a thermophilic single domain FKBP, it was shown that insertions in this PPIase domain are important for chaperone-like activity (54). In contrast, using two well established model substrates, CS and rhodanese, we were able to localize the site for interaction with non-native proteins to the C-terminal part of FKBP52 in this study.…”

Section: Resultsmentioning

confidence: 58%

Localization of the Chaperone Domain of FKBP52

Pirkl¹,

Fischer²,

Modrow³

et al. 2001

Journal of Biological Chemistry

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FKBP52, a multidomain peptidyl prolyl cis/transisomerase (PPIase), is found in complex with the chaperone Hsp90 and the co-chaperone p23. It displays both PPIase and chaperone activity in vitro. To localize these two activities to specific regions of the protein, we created and analyzed a set of fragments of FKBP52. The PPIase activity toward both peptides and proteins is confined entirely to domain 1 (amino acids 1-148). The chaperone activity, however, resides in the C-terminal part of FKBP52, mainly in the region between amino acids 264 and 400 (domain 3). Interestingly, this domain also contains the tetratricopeptide repeats, which are responsible for the binding to C-terminal amino acids of Hsp90. Competition assays with a C-terminal Hsp90 peptide suggest that the non-native protein and Hsp90 are bound by different regions within this domain.

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Section: Resultsmentioning

confidence: 58%

Localization of the Chaperone Domain of FKBP52

Pirkl¹,

Fischer²,

Modrow³

et al. 2001

Journal of Biological Chemistry

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“…These results may indicate that the C-terminal region of the full-length LdCyP, responsible for binding with AdK, was probably not fully accessible due to masking. The fact that the chaperone activity resides in the C-terminal region has also been demonstrated using mammalian FKBP-52 and FK 506-binding protein from thermophilic archaeon (53,54).…”

Section: And References Therein)mentioning

confidence: 89%

A Single-domain Cyclophilin from Leishmania donovaniReactivates Soluble Aggregates of Adenosine Kinase by Isomerase-independent Chaperone Function

Chakraborty¹,

Das²,

Datta³

et al. 2002

Journal of Biological Chemistry

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Disaggregation and reactivation of aggregated proteins by chaperones is well established. However, little is known regarding such kind of function of single-domain small cyclophilins (CyPs). Here we demonstrate that, with increasing concentrations, fully active adenosine kinase (AdK) of Leishmania donovani tends to form soluble aggregates, resulting in inactivation. Using this inactive enzyme as the substrate, it is shown that a CyP from L. donovani (LdCyP) alone can cause complete disaggregation, leading to reactivation of the enzyme. The reactivating ability of LdCyP remains unaffected even in the presence of cyclosporin A and macromolecular crowding agents. The reactivation occurs noncatalytically and is reversible. A truncated LdCyP, devoid of 88 amino acids from the N terminus, is found to be required in near stoichiometric proportion to reactivate AdK, suggesting essentiality of the C-terminal region. Gel filtration and light-scattering experiments together with protein cross-linking studies revealed that both full-length LdCyP and the truncated form directly interact with AdK and convert oligomeric forms of the enzyme to monomeric state. Homology modeling studies suggest that the exposed hydrophobic residues of LdCyP, by interacting with solvent-accessible hydrophobic surface of AdK, pull apart its aggregated inactive oligomers to functional monomers. Clearly, the results are consistent with the interpretation that the higher efficiency of the truncated LdCyP is most likely due to increased exposure of the hydrophobic residues on its surface. These observations, besides establishing L. donovani AdK as one of the model enzymes to study aggregation-disaggregation of proteins, raise the possibility that single-domain small CyPs, under physiological conditions, may regulate the activity of aggregation-prone proteins by ensuring their disaggregation.

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“…Two different model substrate proteins, RNase-T1 (ribonuclease T1) and rhodanese, have been used to study the protein folding activity of a short type archaeal FKBP (84). RNase-T1 is completely refoldable and has two cis peptidyl-prolyl bonds (Tyr38-Pro39 and Ser54-Pro55) (38).…”

Section: Chaperone-like Activity Of a S Hort-type Archaeal Fkbpmentioning

confidence: 99%

“…This PPIase activity of MtFKBP17 is completely inhibited by FK506 ( 84). MtFKBP17 protects aggregation of folding intermediates and elevated the final recovery of rhodanese refolding in dose-dependent fashion (figure 6) (84).…”

Section: Chaperone-like Activity Of a S Hort-type Archaeal Fkbpmentioning

confidence: 99%

“…The PPIase activity of the mutant lacking the flap insertion (FK-dF) was undetectable. The far-UV circular dichroism (CD) spectral analysis revealed that the both bulge and flap insertions are important for a proper conformation of MtFKBP17 (84). While the secondary structure of FK-dB was shown to be changed, 62% of chaperone-like activity of the wild type remained (table 5).…”

Section: Deletion Analysis Of the Short-type Fkbp From M Thermolithomentioning

confidence: 99%

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