Combination of the Human Prolyl Isomerase FKBP12 with Unrelated Chaperone Domains Leads to Chimeric Folding Enzymes with High Activity

Geitner, Anne-Juliane; Schmid, Franz X.

doi:10.1016/j.jmb.2012.04.018

Cited by 18 publications

(22 citation statements)

References 73 publications

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“…Upon fusion with the chaperone domain of SlyD, an FKBP of E. coli, hFKBP12 lost its specificity for leucine or phenyalanine residues on P 1 and was able to isomerize Lys-Pro, Ala-Pro, and Glu-Pro bonds equally well, and with high efficiency (42). The same observation could be made even when chaperone domains of unrelated protein families, such as the protein disulfide isomerase (PDI) of yeast, the chaperonin GroEL, or parvulin SurA of E. coli, were used (43).…”

Section: Modular Structurementioning

confidence: 77%

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Ünal

Steinert

2014

Microbiol Mol Biol Rev

156

146

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SUMMARY Initially discovered in the context of immunomodulation, peptidyl-prolyl cis/trans isomerases (PPIases) were soon identified as enzymes catalyzing the rate-limiting protein folding step at peptidyl bonds preceding proline residues. Intense searches revealed that PPIases are a superfamily of proteins consisting of three structurally distinguishable families with representatives in every described species of prokaryote and eukaryote and, recently, even in some giant viruses. Despite the clear-cut enzymatic activity and ubiquitous distribution of PPIases, reports on solely PPIase-dependent biological roles remain scarce. Nevertheless, they have been found to be involved in a plethora of biological processes, such as gene expression, signal transduction, protein secretion, development, and tissue regeneration, underscoring their general importance. Hence, it is not surprising that PPIases have also been identified as virulence-associated proteins. The extent of contribution to virulence is highly variable and dependent on the pleiotropic roles of a single PPIase in the respective pathogen. The main objective of this review is to discuss this variety in virulence-related bacterial and protozoan PPIases as well as the involvement of host PPIases in infectious processes. Moreover, a special focus is given to Legionella pneumophila macrophage infectivity potentiator (Mip) and Mip-like PPIases of other pathogens, as the best-characterized virulence-related representatives of this family. Finally, the potential of PPIases as alternative drug targets and first tangible results are highlighted.

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Section: Modular Structurementioning

confidence: 77%

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Ünal

Steinert

2014

Microbiol Mol Biol Rev

156

146

View full text Add to dashboard Cite

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“…Chaperone activity has been reported only for two other microbial single-domain PPIases, cyclophilin LdCyP from Leishmania donovani and FKBP AvfkbX from Azotobacter vinelandii (56,57). Different chimeric PPIases with additional chaperone domains have been shown to be very efficient and fast in protein refolding, which may be interesting for various applications (61,62 We also found that FkpA positively influences the activity of CS in vitro, in particular at lower temperatures (Fig. 5).…”

Section: Discussionmentioning

confidence: 63%

Single-Domain Peptidyl-Prolyl cis / trans Isomerase FkpA from Corynebacterium glutamicum Improves the Biomass Yield at Increased Growth Temperatures

Kallscheuer

Bott

Ooyen

et al. 2015

Appl Environ Microbiol

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Peptidyl-prolyl cis/trans isomerases (PPIases) catalyze the rate-limiting protein folding step at peptidyl bonds preceding proline residues and were found to be involved in several biological processes, including gene expression, signal transduction, and protein secretion. Representative enzymes were found in almost all sequenced genomes, including Corynebacterium glutamicum, a facultative anaerobic Gram-positive and industrial workhorse for the production of amino acids. In C. glutamicum, a predicted single-domain FK-506 (tacrolimus) binding protein (FKBP)-type PPIase (FkpA) is encoded directly downstream of gltA, which encodes citrate synthase (CS). This gene cluster is also present in other Actinobacteria. Here we carried out in vitro and in vivo experiments to study the function and influence of predicted FkpA in C. glutamicum. In vitro, FkpA indeed shows typical PPIase activity with artificial substrates and is inhibited by FK-506. Furthermore, FkpA delays the aggregation of CS, which is also inhibited by FK-506. Surprisingly, FkpA has a positive effect on the activity and temperature range of CS in vitro. Deletion of fkpA causes a 50% reduced biomass yield compared to that of the wild type when grown at 37°C, whereas there is only a 10% reduced biomass yield at the optimal growth temperature of 30°C accompanied by accumulation of 7 mM L-glutamate and 22 mM 2-oxoglutarate. Thus, FkpA may be exploited for improved product formation in biotechnical processes. Comparative transcriptome analysis revealed 69 genes which exhibit >2-fold mRNA level changes in C. glutamicum ⌬fkpA, giving insight into the transcriptional response upon mild heat stress when FkpA is absent.T he soil microorganism Corynebacterium glutamicum is widely used in large-scale industrial processes to produce the flavorenhancing amino acid L-glutamate and the feed additive L-lysine (2,900,000 and 1,950,000 tons/year; Ajinomoto). C. glutamicum, which grows on a variety of carbon sources, also has the potential for the production of several organic acids and other commercially interesting compounds (see, for example, references 1, 2, and 3 and references therein). Parameters such as hyperoptimal temperatures and osmotic stress play an important role in biotechnical processes (4, 5). The optimum growth temperature of C. glutamicum is about 30°C to 33°C, although it is able to grow at temperatures ranging from 15°C to 40°C (6). As a soil organism, C. glutamicum is able to adapt to fast-changing conditions, including pH (7), salinity (8), and also temperature. Adaptation mechanisms of C. glutamicum toward nonoptimal growth temperatures include the heat shock response induced at temperatures above 40°C (9-11) and the cold shock response induced below 20°C (12), both involving distinct sets of chaperones.Adaptation mechanisms of cells toward temperature, including the responses to heat shock and cold shock as well as protein chaperones, have been reviewed many times in several model systems (see, for example, references 13-15, and 16). Beside chapero...

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“…As another example, the insert-inflap (IF) domain (46) from E. coli SlyD confers chaperone activity to this FKBP enzyme and transfer of this domain to the human FKBP12 is sufficient for improved substrate affinity by the chimeric protein (47). Similar effects have been noted for the transfer of chaperone domains from non-FKBP proteins such as GroEL and SurA (48). For Fpr4, the N-terminal domain may function in a similar capacity to restrict the substrate repertoire.…”

Section: Discussionmentioning

confidence: 82%

Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization

Monneau

Soufari

Nelson

et al. 2013

Journal of Biological Chemistry

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Background:The yeast histone chaperone Fpr4 harbors a peptidyl-prolyl isomerase domain of the FK506-binding protein (FKBP) family. Results: Catalytic efficiency toward three peptides from histone H3 relates to residues flanking the central proline. Conclusion: Substrate residues C-terminal to the proline dictate isomerase activity by Fpr4. Significance: The findings reveal new molecular details of substrate peptide recognition by the peptidyl-prolyl isomerase domain.

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Combination of the Human Prolyl Isomerase FKBP12 with Unrelated Chaperone Domains Leads to Chimeric Folding Enzymes with High Activity

Cited by 18 publications

References 73 publications

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Microbial Peptidyl-Prolyl cis / trans Isomerases (PPIases): Virulence Factors and Potential Alternative Drug Targets

Single-Domain Peptidyl-Prolyl cis / trans Isomerase FkpA from Corynebacterium glutamicum Improves the Biomass Yield at Increased Growth Temperatures

Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization

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