Peptide Bond cis/trans Isomerases: A Biocatalysis Perspective of Conformational Dynamics in Proteins

Schiene‐Fischer, Cordelia; Aumüller, Tobias; Fischer, Gunter

doi:10.1007/128_2011_151

Cited by 60 publications

(69 citation statements)

References 239 publications

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“…This enzymatic activity catalyzes the isomerization of peptidyl-prolyl bonds between cis and trans conformations, and therefore influences target protein folding and function (12,13). FKBP52 contains additional functional domains, such as a tetratricopeptide repeat domain that serves as a binding site for molecular chaperone heat shock protein with a molecular mass of 90 kDa (14) and for which chaperone activity was observed (15).…”

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Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy

Giustiniani

Chambraud

Sardin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Tau protein is the major component of intracellular filaments observed in a number of neurodegenerative diseases known as tauopathies. The pathological mutant of Tau containing a prolineto-leucine mutation at position 301 (P301L) leads to severe human tauopathy. Here, we assess the impact of FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52), an immunophilin protein that interacts with physiological Tau, on Tau-P301L activity. We identify a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrate FKBP52's ability to induce the formation of Tau-P301L oligomers. EM analysis shows that Tau-P301L oligomers, induced by FKBP52, can assemble into filaments. In the transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons. This result correlates with a significant reduction of pT181 pathological phosphorylated Tau and with recovery of the stereotypic escape response behavior. Collectively, FKBP52 appears to be an endogenous candidate that directly interacts with the pathogenic Tau-P301L and modulates its function in vitro and in vivo.FKBP | Tau assembly | Tau-P301L dementia T au is a MAP mainly found in neurons (1, 2), which becomes hyperphosphorylated in several neurodegenerative diseases known as tauopathies and forms intraneuronal aggregates called neurofibrillary tangles (NFTs) (3-5). The accumulation of Tau aggregates is a multistep process that involves transient species, and growing evidence suggests that not only the NFTs but equally small oligomeric species contribute to Tau-mediated neurotoxicity (6-8). The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) is identified in frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) (9). Larvae of the zebrafish overexpressing the Tau-P301L mutant protein show defects in motoneuron development early on, and in this model, different Tau phosphoforms are associated with its pathological state (10).The FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52) belongs to the immunophilin family and presents rotamase activity inhibited by FK506 binding (11). This enzymatic activity catalyzes the isomerization of peptidyl-prolyl bonds between cis and trans conformations, and therefore influences target protein folding and function (12, 13). FKBP52 contains additional functional domains, such as a tetratricopeptide repeat domain that serves as a binding site for molecular chaperone heat shock protein with a molecular mass of 90 kDa (14) and for which chaperone activity was observed (15).A novel role of FKBP52 has recently emerged because it binds directly to tubulin and induces tubulin depolymerization in vitro (16). Biochemical characterization of FKBP52 showed that it interacts with Tau, especially its hyperphosphorylated form, and demonstrated an antagonist effect of FKBP52 on Tau's function in tubulin assembly ...

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Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy

Giustiniani

Chambraud

Sardin

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…More complex and physiologically relevant protein systems can now be studied in single-molecule mechanical assays. A whole enzyme machinery is involved in catalyzing cis-trans isomerization of proteins in vivo (11,12,37). Therefore, it will be an important task for the future to study the influence of cis/trans-prolyl isomerases (e.g., FK506 bindig protein, cyclophilin, parvulin) on peptide chains directly on the singlemolecule level.…”

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confidence: 99%

Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin

Rognoni

Möst

Žoldák

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Proline switches, controlled by cis-trans isomerization, have emerged as a particularly effective regulatory mechanism in a wide range of biological processes. In this study, we use single-molecule mechanical measurements to develop a full kinetic and energetic description of a highly conserved proline switch in the force-sensing domain 20 of human filamin and how prolyl isomerization modulates the force-sensing mechanism. Proline isomerization toggles domain 20 between two conformations. A stable cis conformation with slow unfolding, favoring the autoinhibited closed conformation of filamin's force-sensing domain pair 20-21, and a less stable, uninhibited conformation promoted by the trans form. The data provide detailed insight into the folding mechanisms that underpin the functionality of this binary switch and elucidate its remarkable efficiency in modulating force-sensing, thus combining two previously unconnected regulatory mechanisms, proline switches and mechanosensing. O wing to its ring structure (Fig. 1A), the peptidyl-prolyl bond is special among the peptide bonds in that it can populate slowly exchanging cis and trans conformations with similar probability (1). Therefore, proline residues can drastically affect the kinetics of folding (2, 3) as well as conformational changes of proteins (4, 5). Although most native protein conformations require trans prolines, there are a number of examples where native cis prolines have been reported (1,(6)(7)(8). In a few cases, both cis and trans conformations can be accommodated in the folded state thus leading to two distinct native states (9-11). Beyond its importance for protein folding, peptidyl-prolyl isomerization has also been discussed as a molecular timer switch regulating different functional conformations of proteins (5, 12).Filamins are essential actin cross-linkers as well as mechanosignaling hubs in the cytoskeleton. Recently, a special conformation in the rod 2 region of filamin has been shown to act as a force-sensing region mediating the interaction to transmembrane receptors like integrins or the von Willebrand receptor glycoprotein Ib (GPIb) (13-15) (Fig. 1B). Lad et al. (13) have shown that the first β-strand of domain 20 (FLNa20) of human filamin A binds to the subsequent domain 21 (FLNa21) thus covering and autoinhibiting its transmembrane receptor-binding site forming the domain pair shown in Fig. 1B. This domain pair has a mechanosensor function (15, 16). Mechanical force transmitted through the cytoskeleton leads to the opening of the domain pair and an increase in receptor-binding affinity of up to 17-fold (15). The crystal structure of FLNa20 exhibits a native cis proline just in front of the last β-strand (Fig. 1B, Inset). Interestingly, a multiple-sequence alignment shows that this cis proline residue is strictly conserved in all available 3D structures of filamin Ig-like domains (Fig. S1).Although proline isomerization has been investigated in numerous bulk studies, the structural heterogeneity caused by a native-state isomerization...

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“…PPIases catalyze both cis¡trans and trans¡cis peptide bond isomerizations. The resulting changes in protein conformation can have profound functional consequences, such as altering protein-protein interactions, protein stability, or the suitability of a protein as a target for further modifications, e.g., phosphorylation/dephosphorylation (46,47,56).Three classes of PPIases have been identified (5). The parvulin family of PPIases, of which Ess1 (essential 1) protein in Saccharomyces cerevisiae is the founding eukaryotic member, is distinct from the well-studied cyclophilin and FK506-binding protein (FKBP) families, which are targets of immunosuppressive drugs.…”

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Multiple Roles for the Ess1 Prolyl Isomerase in the RNA Polymerase II Transcription Cycle

Atencio

Barnes

et al. 2012

Molecular and Cellular Biology

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The Ess1 prolyl isomerase in Saccharomyces cerevisiae regulates RNA polymerase II (pol II) by isomerizing peptide bonds within the pol II carboxy-terminal domain (CTD) heptapeptide repeat (YSPTSPS). Ess1 preferentially targets the Ser5-Pro6 bond when Ser5 is phosphorylated. Conformational changes in the CTD induced by Ess1 control the recruitment of essential cofactors to the pol II complex and may facilitate the ordered transition between initiation, elongation, termination, and RNA processing. Here, we show that Ess1 associates with the phospho-Ser5 form of polymerase in vivo, is present along the entire length of coding genes, and is critical for regulating the phosphorylation of Ser7 within the CTD. In addition, Ess1 represses the initiation of cryptic unstable transcripts (CUTs) and is required for efficient termination of mRNA transcription. Analysis using strains lacking nonsense-mediated decay suggests that as many as half of all yeast genes depend on Ess1 for efficient termination. Finally, we show that Ess1 is required for trimethylation of histone H3 lysine 4 (H3K4). Thus, Ess1 has direct effects on RNA polymerase transcription by controlling cofactor binding via conformationally induced changes in the CTD and indirect effects by influencing chromatin modification. P eptidyl-prolyl isomerases (PPIases) are enzymes that noncovalently modify target proteins by catalyzing the rotation of the peptide bond preceding proline residues. PPIases catalyze both cis¡trans and trans¡cis peptide bond isomerizations. The resulting changes in protein conformation can have profound functional consequences, such as altering protein-protein interactions, protein stability, or the suitability of a protein as a target for further modifications, e.g., phosphorylation/dephosphorylation (46,47,56).Three classes of PPIases have been identified (5). The parvulin family of PPIases, of which Ess1 (essential 1) protein in Saccharomyces cerevisiae is the founding eukaryotic member, is distinct from the well-studied cyclophilin and FK506-binding protein (FKBP) families, which are targets of immunosuppressive drugs. In yeast, Ess1 is required for growth (20), and its human homolog, Pin1, complements yeast ess1 mutants (32). Pin1 has been linked to a number of signaling pathways in human cells and seems to target a wide variety of proteins for isomerization (33,70). In contrast, extensive genetic studies have thus far identified only RNA polymerase II (pol II) as the target of Ess1 in yeast (21,27,65).Within the RNA pol II complex, Ess1 targets the carboxy-terminal domain (CTD) of the largest subunit, Rpb1 (38, 65), which is composed of 26 repeats of the heptapeptide Y 1 S 2 P 3 T 4 S 5 P 6 S 7 (62). Each repeat contains two potential Ess1 substrate binding sites (S-P), where the serines are known to be phosphorylated (24,43). In vitro, Ess1 binds and isomerizes phosphorylated Ser5-Pro6 (pSer5-Pro6) within the heptad repeat about 5-fold better than pSer2-Pro3 (17). Ess1 stimulates pSer5-Pro6 isomerization within peptide substrates fr...

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Peptide Bond cis/trans Isomerases: A Biocatalysis Perspective of Conformational Dynamics in Proteins

Cited by 60 publications

References 239 publications

Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy

Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy

Force-dependent isomerization kinetics of a highly conserved proline switch modulates the mechanosensing region of filamin

Multiple Roles for the Ess1 Prolyl Isomerase in the RNA Polymerase II Transcription Cycle

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